2-phenyl-3,4-dihydropyrrolo[2,1 -f] [1,2,4]triazinone derivatives as phosphodiesterase inhibitors and uses thereof

ABSTRACT

The present invention relates to compounds of formula I 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein
 
R 1  is C 1 -C 3 alkyl optionally substituted with F, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy;
 
X represents a bond or C 1 -C 3 alkylene optionally substituted with OH, ONO, ONO 2 ;
 
R 2  is H, OH, ONO, ONO 2 , C(O)OH, C(O)OC 1 -C 3 alkyl, CHO, CN, C 1 -C 3 alkoxy, OC(O)H, OC(O)—C 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)OC 1 -C 3 alkyl, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7 , S(O 0-2 )C 1 -C 3 alkyl, CR 8 ═N—OR 9 , CR 8 ═N—NR 10 R 11 , CR 8 ═NR 12  or CR 8 ═N—ONO 2 ;
 
R 3  is C 1 -C 6 alkyl optionally substituted with F, OH, ONO, ONO 2 , C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl;
 
R 4  is C 1 -C 6 alkyl optionally substituted with C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, F, ONO, ONO 2 ; C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl;
 
R 5  is H, SO 2 NR 13 R 14 , NHSO 2 NR 13 R 14 ;
 
R 6  is H or C 1 -C 3 alkyl;
 
R 7  is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl substituted with phenyl, benzyl or a heterocyclic ring, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C 1 -C 3 alkyl, F;
 
R 8  is H, CH 3  or C 2 H 5 ;
 
R 9 : H, C 1 -C 3 alkyl optionally substituted with OH, ONO, ONO 2 , CN, COOH, COOC 1 -C 3 alkyl, C 1 -C 3 alkoxy, OC(O)H, OC(O)—C 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)OC 1 -C 3 alkyl, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7 , S(O 0-2 )C 1 -C 3 alkyl;
 
R 10  and R 11  are each independently H, C 1 -C 3 alkyl optionally substituted with OH, ONO, ONO 2 , CN, COOH, COOC 1 -C 3 , C 1 -C 3 alkoxy, OC(O)H, OC(O)—C 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)OC 1 -C 3 alkyl, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7 , S(O 0-2 )C 1 -C 3 alkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine and homopiperazine, wherein said heterocyclic ring is optionally substituted with C 1 -C 3  alkyl;
 
R 12  is C 1 -C 3  alkyl optionally substituted with OH, ONO, ONO 2 , CN, COOH, COOC 1 -C 3 alkyl, C 1 -C 3 alkoxy, OC(O)H, OC(O)—C 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)OC 1 -C 3 alkyl, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7 , S(O 0-2 )C 1 -C 3 alkyl;
 
R 13  and R 14  are each independently H or C 1 -C 6 alkyl optionally substituted with F, OH, ONO, ONO 2 , COOH, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring is optionally substituted with R 15 ;
 
R 15  is C 1 -C 6 alkyl optionally substituted with halogen, OH, ONO, ONO 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, COOR 16 , NR 17 R 18 , C═NR 19 , or with a tetrazole group which is optionally substituted with C 1 -C 3 alkyl; or a heteroaryl ring which is optionally substituted with F, wherein the at least one heteroatom of said heteroaryl ring is nitrogen;
 
R 16  is H, or C 1 -C 4 alkyl optionally substituted with F, OH, ONO, ONO 2 , NR 17 R 18 , or with a heteroaryl ring, wherein the at least one heteroatom of said heteroaryl ring is nitrogen, and wherein preferably said heteroaryl ring is selected from pyrrolidine, piperidine, piperazine, morpholine, pyrrole, and imidazole, wherein nitrogen atom is directly bound to C 1 -C 4  alkyl;
 
R 17  and R 18  are each independently H or C 1 -C 4 alkyl optionally substituted with ONO, ONO 2 ; R 19  is C 1 -C 4 alkyl optionally substituted with F, ONO, ONO 2 ; C 3 -C 6 cycloalkyl;
 
and their use in methods of treating or preventing a disease alleviated by inhibition of PDE-5 in a human or in a non-human mammal.

The present invention relates to pharmaceutically useful compounds, inparticular to compounds which are useful in the inhibition of cyclicguanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs), and herebyin particular in the inhibition of type 5 cyclic guanosine3′,5′-monophosphate phosphodiesterase (cGMP PDES). The compounds of thepresent invention have utility in a variety of therapeutic areas,including male erectile dysfunction (MED), Alzheimer's disease,pulmonary artery hypertension (PAH), endothelial dysfunction (ED),benign prostatic hyperplasia (BPH) and lower urinary tract symptoms(LUTS), priapism, cystic fibrosis, peripheral vascular disease, vasculardisorders such as Raynaud's disease, systemic sclerosis (SSc),scleroderma, diabetes, and in particular for wound healing, inparticular chronic wound healing, diabetic foot, diabetic foot ulcer,leg ulcer and diabetic neuropathy.

RELATED ART

Phosphodiesterases (PDEs) are enzymes that catalyzes the hydrolysis andthus the degradation of cyclic adenosine monophosphate (cAMP) and cyclicguanosine monophosphate (cGMP) and thereby regulates intracellularlevels of second messengers. Inhibition of PDEs leads to increasingintracellular concentrations of endogenous cAMP/cGMP. Therefore,inhibition of PDE can mediate a variety of physiological mechanisms atdifferent cell and organ levels.

Phosphodiesterase type 5 (PDE5) hydrolyses cyclic guanylatemonophosphate (cGMP) specifically to 5′ GMP. The selective inhibition ofPDE5 has been validated as a relevant approach and strategies directedto promote inhibition of PDE5 activity have been applied as therapeutictools, in particular, in neuronal and cardiovascular conditions.Moreover, the introduction of PDE5 inhibitors has revolutionized thetreatment of male erectile dysfunction (MED) (Dobhal T, Kaur S, PrakashSharma O, Hari Kumar S L, Critical Review in Pharmaceutical Sciences(2012) 1(3):13-27). Several PDE5 inhibitors are on the market and arecharacterized particularly for MED or pulmonary hypertension (PH), inparticular PAH (Papapetropoulos A, Hobbs A J, Topouzis S, BritishJournal of Pharmacology (2015) 172:1397-1414; Monica F Z, Murad F, BianK, OA Biochemistry (2014) March 11; 2(1):3; Beedimani R S, Kalmath B,Int J Pharm Bio Sci (2014) 5(2): 530-539; Wronski S, Cent European JUrol (2014) 67: 314-318; and references cited therein). Most prominentexamples of PDE5 inhibitors are Sildenafil, Tadalafil and Vardenafilwhich have been described among others, for example, in WO 99/24433, WO01/60825, EP 995′751 and WO 2011/075655.

Beside the success of the known PDE5 inhibitors, there is still a needfor further and in particular more potent PDE5 inhibitors and theirpharmaceutical compositions for use in the therapeutic treatment orprophylaxis of diseases associated with a disturbed cGMP balance.Moreover, and in general, there is still a need for compounds and theirpharmaceutical compositions being beneficial for use in the therapeutictreatment or prophylaxis of diseases associated with a disturbed cGMPbalance.

SUMMARY OF THE INVENTION

We have surprisingly found that the compounds of the present inventionare very potent and selective inhibitors of PDE5. Furthermore, we havesurprisingly found that the compounds of the present invention can betailored to become dual-pharmacology NO-releasing PDE5 inhibitors whichare believed to release NO in addition to its PDE 5 inhibition in a morethan additive fashion. These dual-pharmacology NO-releasing PDE5inhibitors are believed to be highly beneficial for the treatment ofdiabetic patients. Moreover, we have surprisingly found that preferredcompounds of the present invention show even a significantly higher PDE5inhibition activity as compared to known PDE5 inhibitors such assildenafil. As a consequence, the novel pyrrolo triazine compounds ofthe present invention are useful in the therapy and prophylaxis ofdiseases which are associated with a disturbed cGMP balance. Due to thepotent and selective PDE5 inhibition exhibited by compounds of thepresent invention, cGMP levels are elevated, which in turn can give riseto beneficial vasodilatory, anti-vasospastic, anti-platelet,anti-neutrophil, natriuretic and diuretic activities. Furthermore, thetailoring of the inventive compounds to dual-pharmacology NO-releasingPDE5 inhibitors allows the release of nitric oxide for activating thesoluble guanylate cyclase as well as the PDE 5 inhibition in a more thanadditive fashion. Thus, the compounds of the present invention haveutility in variety of therapeutic areas where a disturbed cGMP balanceoccurred and/or PDE5 inhibition is thought to be beneficial. Some of thepreferred therapeutic areas are wound healing, in particular chronicwound healing, diabetic foot, diabetic foot ulcer, leg ulcer, Raynaud's,male erectile dysfunction, female sexual dysfunction, Alzheimer'sdisease, diabetes, hair loss, skin aging, vascular aging, pulmonaryartery hypertension and chronic heart failure.

Thus, in a first aspect, the present invention provides for a compoundof formula I

or pharmaceutically acceptable salt, solvate or hydrate thereof, whereinR₁ is C₁-C₃alkyl optionally substituted with F, C₃-C₆cycloalkyl,C₁-C₃alkoxy;X represents a bond or C₁-C₃alkylene optionally substituted with OH,ONO, ONO₂;R₂ is H, OH, ONO, ONO₂, C(O)OH, C(O)OC₁-C₃alkyl, CHO, CN, C₁-C₃alkoxy,OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇,S(O₀₋₂)C₁-C₃alkyl, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂ or CR₈═N—ONO₂;R₃ is C₁-C₆alkyl optionally substituted with F, OH, ONO, ONO₂,C₁-C₃alkoxy, C₃-C₆cycloalkyl; C₃-C₆cycloalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl;R₄ is C₁-C₆alkyl optionally substituted with C₃-C₆cycloalkyl, C₁-C₆alkoxy, F, ONO, ONO₂; C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl;R₅ is H, SO₂NR₁₃R₁₄, NHSO₂NR₁₃R₁₄;R₆ is H or C₁-C₃alkyl;R₇ is H, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ alkyl substituted with phenyl,benzyl or a heterocyclic ring, wherein said phenyl, benzyl or saidheterocyclic ring are independently optionally substituted by C₁-C₃alkyl, F;R₈ is H, CH₃ or C₂H₅;R₉ is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH,COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl;R₁₀ and R₁₁ are each independently H, C₁-C₃alkyl optionally substitutedwith OH, ONO, ONO₂, CN, COOH, COOC₁-C₃, C₁-C₃alkoxy, OC(O)H,OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇,S(O₀₋₂)C₁-C₃alkyl; or together with the nitrogen atom to which they areattached form a heterocyclic ring, wherein preferably said heterocyclicring is selected from aziridine, azetidine, pyrollidine, piperidine,morpholine, piperazine and homopiperazine, wherein said heterocyclicring is optionally substituted with C₁-C₃ alkyl;R₁₂ is C₁-C₃ alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH,COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl;R₁₃ and R₁₄ are each independently H or C₁-C₆alkyl optionallysubstituted with F, OH, ONO, ONO₂, COOH, C₁-C₃alkoxy, C₃-C₆cycloalkyl;or together with the nitrogen atom to which they are attached form aheterocyclic ring, wherein preferably said heterocyclic ring is selectedfrom aziridine, azetidine, pyrollidine, piperidine, morpholine,piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring isoptionally substituted with R₁₅;R₁₅ is C₁-C₆alkyl optionally substituted with halogen, OH, ONO, ONO₂,C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉, or with atetrazole group which is optionally substituted with C₁-C₃alkyl; or aheteroaryl ring which is optionally substituted with F, wherein the atleast one heteroatom of said heteroaryl ring is nitrogen;R₁₆ is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂,NR₁₇R₁₈, or with a heteroaryl ring, wherein the at least one heteroatomof said heteroaryl ring is nitrogen, and wherein preferably saidheteroaryl ring is selected from pyrrolidine, piperidine, piperazine,morpholine, pyrrole, and imidazole, wherein nitrogen atom is directlybound to C₁-C₄ alkyl;R₁₇ and R₁₈ are each independently H or C₁-C₄alkyl optionallysubstituted with ONO, ONO₂;R₁₉ is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂;C₃-C₆cycloalkyl.

In a further aspect, the present invention provides for a pharmaceuticalcomposition comprising at least one of the inventive compound of formulaI, or a pharmaceutically acceptable salt, solvate or hydrate thereof,and a pharmaceutically acceptable excipient, adjuvant, or carrier.

In another aspect, the present invention provides for a compound offormula I, or a pharmaceutical composition, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, for use in a method oftreating or preventing a disease alleviated by inhibition of PDE-5 in ahuman or in a non-human mammal, preferably in a human. Preferably, saiddisease is selected from wound healing, chronic wound healing, diabeticfoot, diabetic foot ulcer, leg ulcer, Raynaud's disease, male erectiledysfunction, female sexual dysfunction, diabetes, hair loss, skin aging,vascular aging, pulmonary artery hypertension; stable, unstable andvariant (Prinzmetal) angina; hypertension, pulmonary hypertension,chronic obstructive pulmonary disease, congestive heart failure, renalfailure, atherosclerosis, conditions of reduced blood vessel patency,peripheral vascular disease, vascular disorders, systemic sclerosis(SSc), scleroderma, morphea, inflammatory diseases, stroke, bronchitis,chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy,Idiopathic pulmonary fibrosis (IPF), peyronic's disease, glaucoma or adisease characterized by disorders of gut motility like irritable bowelsyndrome, liver fibrosis, Alzheimer's disease and chronic heart failure,wherein further preferably said disease is selected from wound healing,chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer,diabetic neuropathy, peripheral vascular disease, vascular disorders,Raynaud's disease, systemic sclerosis (SSc), scleroderma, diabetes,pulmonary artery hypertension, male erectile dysfunction, and whereinagain further preferably said disease is selected from wound healing,chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer anddiabetic neuropathy.

In again another aspect, the present invention provides for a compoundof formula IV

wherein X, R₁, R₂, R₃, R₄, R₅ are defined as for the compound of formulaI.

In again another aspect, the present invention provides for a processfor the preparation of a compound of formula I,

wherein said process comprises:

-   -   (a) reaction of a compound of formula II with a benzoic acid        derivative of formula III in an aprotic or a protic solvent to        generate a compound of formula IV

-   -   (b) cyclization of said compound of formula IV to yield compound        of formula I, wherein X, R₁, R₂, R₃, R₄, and R₅ are defined as        for the compound of formula I.

In again another aspect, the present invention provides for a processfor the preparation of a compound of formula I, wherein said processcomprises

-   -   (a) reaction of a compound of formula VI with a benzoyl chloride        derivative of formula VIA to generate a compound of formula VII

-   -   (b) hydrolysis of the ester compound of formula VII to an acid        derivative of formula VIII

-   -   (c) amination of said compound of formula VIII to yield a        compound of formula IV

-   -   (d) cyclization of said compound of formula IV to yield compound        of formula I,        wherein X, R₁, R₂, R₃, R₄, and R₅ are defined as for the        compound of formula I; and        wherein R′ is C₁-C₄ alkyl, benzyl, 4-alkoxybenzyl.

In again another aspect, the present invention provides for a processfor the preparation of a compound of formula I, wherein said processcomprises conversion of compound of formula IA to yield compound offormula I

wherein X, R₁, R₂, R₃, R₄, and R₅ are defined as for the compound offormula I in any one of the claims 1 to 8.

Further aspects and embodiments of the present invention will be becomeapparent as this description continues.

DESCRIPTION OF THE FIGURES

FIG. 1: Concentration dependent measurements of cyclic guanosine3′-5′-monophosphate (cGMP) in human pulmonary artery smooth muscle cells(hPASMC) incubated in presence of the compounds of the inventions or thereference PDE5 inhibitor sildenafil.

FIG. 1A: Concentration dependent measurement of cGMP in hPASMC incubatedfor 15 min in presence of inventive compound 1r in concentrations of1×10⁻¹⁶M (0.1 fM)-1×10⁻⁷M (100 nM).

FIG. 1B: Concentration dependent measurement of cGMP in hPASMC incubatedfor 30 min in presence of inventive compound 1v in concentrations of1×10⁻¹²M (1 pM)-1×10⁻⁷M (100 nM).

FIG. 1C: Concentration dependent measurement of cGMP in hPASMC incubatedfor 15 min in presence of reference PDE5 inhibitor sildenafil inconcentrations of 1×10⁻¹⁰M (0.1 nM)-1×10⁻⁷M (100 nM).

FIG. 2: Concentration dependent relaxation by 1v, 1r, sildenafil ofphenylephrine-precontracted rat aortic rings with intact endothelium(FIG. 2A), exposed to 25 mM glucose for 1 h (FIG. 2B), in presence ofL-NAME (100 μM) (FIG. 2C), following mechanical removal of intactendothelium (FIG. 2D). Results are depicted as the means±SEM from 16-20preparations.

FIG. 3: Non-linear regression (Graph Pad Prism 7.01) of theconcentration dependent relaxation by 1v, 1r, sildenafil ofphenylephrine-precontracted rat aortic rings with intact endothelium(FIG. 3A), exposed to 25 mM glucose for 1 h (FIG. 3B), in presence ofL-NAME (100 μM) (FIG. 3C), following mechanical removal of intactendothelium (FIG. 3D) depicted in FIG. 2. Results are shown as themeans±SEM from 16-20 preparations. The stippled line indicates the 40%inhibition level.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs.

We have surprisingly found that the compounds of formula I of thepresent invention are very potent and selective inhibitors of PDE5.Furthermore, we have surprisingly found that the compounds of thepresent invention can be tailored to become dual-pharmacologyNO-releasing PDE5 inhibitors which are believed to release NO inaddition to its PDE 5 inhibition in a more than additive fashion.Moreover, preferred compounds of the present invention show even asignificantly higher PDE5 inhibition activity as compared to known PDE5inhibitors such as sildenafil.

Thus, in a first aspect, the present invention provides for a compoundof formula I

or pharmaceutically acceptable salt, solvate or hydrate thereof, whereinR₁ is C₁-C₃alkyl optionally substituted with F, C₃-C₆cycloalkyl,C₁-C₃alkoxy;X represents a bond or C₁-C₃alkylene optionally substituted with OH,ONO, ONO₂;R₂ is H, OH, ONO, ONO₂, C(O)OH, C(O)OC₁-C₃alkyl, CHO, CN, C₁-C₃alkoxy,OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇,S(O₀₋₂)C₁-C₃alkyl, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂ or CR₈═N—ONO₂;R₃ is C₁-C₆alkyl optionally substituted with F, OH, ONO, ONO₂,C₁-C₃alkoxy, C₃-C₆cycloalkyl; C₃-C₆cycloalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl;R₄ is C₁-C₆alkyl optionally substituted with C₃-C₆cycloalkyl,C₁-C₆alkoxy, F, ONO, ONO₂; C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl;R₅ is H, SO₂NR₁₃R₁₄, NHSO₂NR₁₃R₁₄;R₆ is H or C₁-C₃alkyl;R₇ is H, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkyl substituted with phenyl,benzyl or a heterocyclic ring, wherein said phenyl, benzyl or saidheterocyclic ring are independently optionally substituted byC₁-C₃alkyl, F;R₈ is H, CH₃ or C₂H₅;R₉ is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH,COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl;R₁₀ and R₁₁ are each independently H, C₁-C₃alkyl optionally substitutedwith OH, ONO, ONO₂, CN, COOH, COOC₁-C₃, C₁-C₃alkoxy, OC(O)H,OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇,S(O₀₋₂)C₁-C₃alkyl; or together with the nitrogen atom to which they areattached form a heterocyclic ring, wherein preferably said heterocyclicring is selected from aziridine, azetidine, pyrollidine, piperidine,morpholine, piperazine and homopiperazine, wherein said heterocyclicring is optionally substituted with C₁-C₃ alkyl;R₁₂ is C₁-C₃ alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH,COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl;R₁₃ and R₁₄ are each independently H or C₁-C₆alkyl optionallysubstituted with F, OH, ONO, ONO₂, COOH, C₁-C₃alkoxy, C₃-C₆cycloalkyl;or together with the nitrogen atom to which they are attached form aheterocyclic ring, wherein preferably said heterocyclic ring is selectedfrom aziridine, azetidine, pyrollidine, piperidine, morpholine,piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring isoptionally substituted with R₁₅;R₁₅ is C₁-C₆alkyl optionally substituted with halogen, OH, ONO, ONO₂,C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉, or with atetrazole group which is optionally substituted with C₁-C₃alkyl; or aheteroaryl ring which is optionally substituted with F, wherein the atleast one heteroatom of said heteroaryl ring is nitrogen;R₁₆ is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂,NR₁₇R₁₈, or with a heteroaryl ring, wherein the at least one heteroatomof said heteroaryl ring is nitrogen, and wherein preferably saidheteroaryl ring is selected from pyrrolidine, piperidine, piperazine,morpholine, pyrrole, and imidazole, wherein nitrogen atom is directlybound to C₁-C₄ alkyl;R₁₇ and R₁₈ are each independently H or C₁-C₄alkyl optionallysubstituted with ONO, ONO₂;R₁₉ is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂;C₃-C₆cycloalkyl.

Thus, in a further aspect, the present invention provides for a compoundof formula I

or pharmaceutically acceptable salt, solvate or hydrate thereof, whereinR₁ is C₁-C₃alkyl optionally substituted with F, C₃-C₆cycloalkyl,C₁-C₃alkoxy;X represents a bond or C₁-C₃alkylene optionally substituted with OH,ONO, ONO₂;R₂ is OH, ONO, ONO₂, C(O)OH, C(O)OC₁-C₃alkyl, CHO, CN, C₁-C₃alkoxy,OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇,S(O₀₋₂)C₁-C₃alkyl, CR₈═N—OR₉, ×CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂ or CR₈═N—ONO₂;R₃ is C₁-C₆alkyl optionally substituted with F, OH, ONO, ONO₂, C₁-C₃alkoxy, C₃-C₆cycloalkyl; C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl;R₄ is C₁-C₆alkyl optionally substituted with C₃-C₆cycloalkyl, C₁-C₆alkoxy, F, ONO, ONO₂; C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl;R₅ is H, SO₂NR₁₃R₁₄, NHSO₂NR₁₃R₁₄;R₆ is H or C₁-C₃alkyl;R₇ is H, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ alkyl substituted with phenyl,benzyl or a heterocyclic ring, wherein said phenyl, benzyl or saidheterocyclic ring are independently optionally substituted by C₁-C₃alkyl, F;R₈ is H, CH₃ or C₂H₅;R₉ is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH,COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl;R₁₀ and R₁₁ are each independently H, C₁-C₃alkyl optionally substitutedwith OH, ONO, ONO₂, CN, COOH, COOC₁-C₃, C₁-C₃alkoxy, OC(O)H,OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇,S(O₀₋₂)C₁-C₃alkyl; or together with the nitrogen atom to which they areattached form a heterocyclic ring, wherein preferably said heterocyclicring is selected from aziridine, azetidine, pyrollidine, piperidine,morpholine, piperazine and homopiperazine, wherein said heterocyclicring is optionally substituted with C₁-C₃ alkyl;R₁₂ is C₁-C₃ alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH,COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl;R₁₃ and R₁₄ are each independently H or C₁-C₆alkyl optionallysubstituted with F, OH, ONO, ONO₂, COOH, C₁-C₃alkoxy, C₃-C₆cycloalkyl;or together with the nitrogen atom to which they are attached form aheterocyclic ring, wherein preferably said heterocyclic ring is selectedfrom aziridine, azetidine, pyrollidine, piperidine, morpholine,piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring isoptionally substituted with R₁₅;R₁₅ is C₁-C₆alkyl optionally substituted with halogen, OH, ONO, ONO₂,C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉, or with atetrazole group which is optionally substituted with C₁-C₃alkyl; or aheteroaryl ring which is optionally substituted with F, wherein the atleast one heteroatom of said heteroaryl ring is nitrogen;R₁₆ is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂,NR₁₇R₁₈, or with a heteroaryl ring, wherein the at least one heteroatomof said heteroaryl ring is nitrogen, and wherein preferably saidheteroaryl ring is selected from pyrrolidine, piperidine, piperazine,morpholine, pyrrole, and imidazole, wherein nitrogen atom is directlybound to C₁-C₄ alkyl;R₁₇ and R₁₈ are each independently H or C₁-C₄alkyl optionallysubstituted with ONO, ONO₂;R₁₉ is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂;C₃-C₆cycloalkyl.

Each alkyl moiety either alone or as part of a larger group such asalkoxy or alkylene is a straight or branched chain and is preferablyC₁-C₆alkyl, more preferably C₁-C₃alkyl. Examples include methyl, ethyl,n-propyl, prop-2-yl, n-butyl, but-2-yl, 2-methyl-prop-1-yl or2-methyl-prop-2-yl. Examples of an alkoxy include methoxy, ethoxy,propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy,neo-pentoxy, n-hexoxy. As described herein, alkoxy may include furthersubstitutents such as halogen atoms leading to haloalkoxy moieties.

Each alkylene moiety is a straight or branched chain and is, forexample, —CH₂—, —CH₂—CH₂—, —CH(CH₃)—, —CH₂—CH₂—CH₂—, —CH(CH₃)—CH₂—, or—CH(CH₂CH₃)—.

Each cycloalkyl moiety can be in mono- or bi-cyclic form, typically andpreferably in mono-cyclic form, and preferably contains 3 to 8 carbonatoms, more preferably 3 to 7 carbon atoms. Examples of monocycliccycloalkyl groups include cyclopropyl, cyclobutyl and cyclohexyl.

Each alkenyl moiety either alone or as part of a larger group such asalkenyloxy or alkenylene is a straight or branched chain and ispreferably C₂-C₆alkenyl, more preferably C₂-C₄alkenyl. Each moiety canbe of either the (E)- or (Z)-configuration. Examples include vinyl andallyl. A compound of the present invention comprising an alkenyl moietythus may include, if applicable, either said compound with said alkenylmoiety in its (E)-configuration, said compound with said alkenyl moietyin its (Z)-configuration and mixtures thereof in any ratio.

Each alkynyl moiety either alone or as part of a larger group such asalkynyloxy is a straight or branched chain and is preferablyC₂-C₆alkynyl, more preferably C₂-C₄alkynyl. Examples are ethynyl andpropargyl.

Halogen is fluorine, chlorine, bromine, or iodine.

Each haloalkyl moiety either alone or as part of a larger group such ashaloalkoxy is an alkyl group substituted by one or more of the same ordifferent halogen atoms. Examples include difluoromethyl,trifluoromethyl, chlorodifluoromethyl and 2,2,2-trifluoro-ethyl.

The term “heterocyclic ring” refers to a saturated or partiallyunsaturated carbocyclic ring containing one to four heteroatoms selectedfrom nitrogen, oxygen and sulfur as ring members. Such rings do notcontain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygenand sulfur atoms within the ring. Preferred examples are aziridine,azetidine, pyrollidine, piperidine, morpholine, piperazine,homopiperazine, tetrahydrofurane, dioxane,2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, andfurther preferred are aziridine, azetidine, pyrollidine, piperidine,morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptaneand 3,7-diazabicyclo[3,3,0]octane.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom, and preferably up to three heteroatoms selectedfrom nitrogen, oxygen and sulfur as ring members. Heteroaryl rings donot contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacentoxygen and sulfur atoms within the ring. Preferred examples are includepyrrolidine, piperidine, piperazine, morpholine, pyridine, pyrimidine,pyrazine, pyridazine, pyrrole, pyrazole, imidazole, triazole, isoxazole,oxazole, isothiazole, thiazole, tetrazole, furane, and thiophenyl, andfurther preferred are pyrrolidine, piperidine, piperazine, morpholine,pyrrole, and imidazole.

Where a group is said to be optionally substituted, preferably there areoptionally 1-5 substituents, more preferably optionally 1-3substituents, again more preferably optionally 1 or 2 substituents.Where a group is said to be optionally substituted, and where there aremore than one substituents for said optional substitution of said group,said more than one substituents can either be the same or different.

Certain compounds of formula I of the present invention may contain oneor two or more centers of chirality and such compounds may be providedas pure enantiomers or pure diastereoisomers as well as mixtures thereofin any ratio. The compounds of the invention also include all tautomericforms of the compounds of formula I. The compounds of formula I may alsobe solvated, especially hydrated, which are also included in thecompounds of formula I. Solvation and hydration may take place duringthe preparation process.

As a consequence, the compounds of the present invention and, thus, thecompounds of formula I include stereoisomers, geometric isomers andtautomers. Furthermore, the compounds of the present invention and,thus, the compounds of formula I include solvates or hydrates,pharmaceutically acceptable salts, and solvates or hydrates of the saltsthereof.

Compounds of formula I of the present invention include pharmaceuticallyacceptable salts of said compounds. In particular, the term“pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe present invention, in particular acid addition salts. Exemplarysalts include, but are not limited to, salts of physiologicallyacceptable mineral acids, such as hydrochloric acid, sulfuric acid,nitric acid and phosphoric acid, or salts of organic acids, such asmethane-sulfonic acid, p-toluenesulfonic acid, lactic acid, malic acid,tartaric acid, acetic acid, trifluoroacetic acid, citric acid, succinicacid, fumaric acid, maleic acid and salicylic acid. Further examples ofpharmacologically acceptable salts of the compounds of formula I arealkali metal and alkaline earth metal salts such as, for example,sodium, potassium, lithium, calcium or magnesium salts, ammonium saltsor salts of organic bases such as, for example, methylamine,dimethylamine, triethylamine, piperidine, ethylenediamine, lysine,choline hydroxide, meglumine, morpholine or arginine salts. Furtherexamples of pharmaceutically acceptable salts of the compounds offormula I include the hydrochloride, hydrobromide, sulfate, bisulfate,phosphate, hydrogen phosphate, nitrate, acetate, benzoate, succinate,fumarate, maleate, lactate, citrate, benzenesulphonate,p-toluenesulphonate or the like.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the present invention. Examples of solventsthat form solvates include, but are not limited to, water, isopropanol,ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, aceticacid, and ethanolamine. The term “hydrate” refers to the complex wherethe solvent molecule is water.

In a preferred embodiment of the present invention, R₁ is C₁-C₃alkyl. Ina further preferred embodiment, R₁ is CH₃ or C₂H₅, and again furtherpreferably R₁ is CH₃.

In another preferred embodiment, R₃ is C₁-C₆alkyl optionally substitutedwith F, OH, ONO, ONO₂, C₁-C₃alkoxy, C₃-C₆cycloalkyl, C₂-C₄alkenyl. In afurther preferred embodiment, R₃ is C₁-C₄alkyl optionally substitutedwith F, OH, ONO, ONO₂, C₁-C₃alkoxy, C₃-C₆cycloalkyl, C₂-C₄alkenyl. In afurther preferred embodiment, R₃ is C₁-C₄alkyl optionally substitutedwith ONO, ONO₂ or C₃-C₅cycloalkyl. In a further preferred embodiment, R₃is C₁-C₄alkyl optionally substituted with ONO₂ or C₃-C₅cycloalkyl. In afurther preferred embodiment, R₃ is C₁-C₆alkyl, preferably R₃ isC₁-C₄alkyl. In a very preferred embodiment, R₃ is n-propyl.

In another preferred embodiment, R₄ is C₁-C₄alkyl optionally substitutedwith C₃-C₆cycloalkyl, C₁-C₆alkoxy, F, ONO, ONO₂; C₂-C₄alkenyl. In afurther preferred embodiment, R₄ is C₁-C₄alkyl optionally substitutedwith ONO, ONO₂, C₁-C₆alkoxy, or C₃-C₅cycloalkyl. In a further preferredembodiment, R₄ is C₁-C₄alkyl optionally substituted with ONO, ONO₂ orC₁-C₆alkoxy. In a further preferred embodiment, R₄ is C₁-C₄alkyloptionally substituted with ONO₂ or C₁-C₆alkoxy. In a further preferredembodiment, R₄ represents C₁-C₆alkyl, preferably C₁-C₄alky, againpreferably R₄ represents ethyl or n-propyl.

In a further preferred embodiment, said R₁ is C₁-C₃alkyl; R₃ isC₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂, C₁-C₃alkoxy,C₃-C₆cycloalkyl, C₂-C₄alkenyl; and R₄ is C₁-C₄alkyl optionallysubstituted with C₃-C₆cycloalkyl, C₁-C₃alkoxy, F, ONO, ONO₂;C₂-C₄alkenyl.

In a further preferred embodiment, said R₁ is CH₃ or C₂H₅, preferably R₁is CH₃; R₃ is C₁-C₄alkyl optionally substituted with ONO₂ orC₃-C₅cycloalkyl, preferably R₃ is n-propyl; and R₄ is C₁-C₄alkyloptionally substituted with ONO₂ or C₃-C₅cycloalkyl, preferably R₄ isethyl or n-propyl.

In a further preferred embodiment, said R₁₃ and R₁₄ together with thenitrogen atom to which they are attached form a heterocyclic ring,wherein said heterocyclic ring is selected from aziridine, azetidine,pyrollidine, piperidine, morpholine, piperazine, homopiperazine,2,5-diazabicyclo-[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane,wherein said heterocyclic ring is optionally substituted with R₁₅; R₁₅is C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂,C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉; R₁₆ is H, orC₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂; R₁₇ and R₁₈ areeach independently H or C₁-C₄alkyl optionally substituted with ONO,ONO₂, preferably R₁₇ and R₁₈ are each independently H or C₁-C₄alkyloptionally substituted with ONO₂; R₁₉ is C₁-C₄alkyl optionallysubstituted with F, ONO, ONO₂, preferably R₁₉ is C₁-C₄alkyl optionallysubstituted with ONO₂.

In a further preferred embodiment, said R₅ is SO₂NR₁₃R₁₄, NHSO₂NR₁₃R₁₄;said R₁₃ and R₁₄ together with the nitrogen atom to which they areattached form a heterocyclic ring, wherein said heterocyclic ring isselected from aziridine, azetidine, pyrollidine, piperidine, morpholine,piperazine, homopiperazine, 2,5-diazabicyclo-[2,2,1]heptane and3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring isoptionally substituted with R₁₅; said R₁₅ is C₁-C₄alkyl optionallysubstituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, COOR₁₆, NR₁₇R₁₈,C═NR₁₉; R₁₆ is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO,ONO₂; said R₁₇ and R₁₈ are each independently H or C₁-C₄alkyl optionallysubstituted with ONO, ONO₂; said R₁₉ is C₁-C₄alkyl optionallysubstituted with F, ONO, ONO₂.

In a further preferred embodiment, said R₅ is SO₂NR₁₃R₁₄, wherein R₁₃and R₁₄ are each independently H or together with the nitrogen atom towhich they are attached form a mono-cyclic ring selected from imidazol,aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazineand homopiperazine optionally substituted with R₁₅; said R₁₅ isC₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂,C₁-C₃alkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉; R₁₆ is H, or C₁-C₄alkyl optionallysubstituted with F, OH, ONO, ONO₂; said R₁₇ and R₁₈ are eachindependently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂;said R₁₉ is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂.

In a further preferred embodiment, said R₅ is SO₂NR₁₃R₁₄, wherein R₁₃and R₁₄ together with the nitrogen atom to which they are attached forma mono-cyclic ring selected from imidazol, aziridine, azetidine,pyrrolidine, piperidine, morpholine, piperazine and homopiperazineoptionally substituted with R₁₅; said R₁₅ is C₁-C₄alkyl optionallysubstituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, COOR₁₆, NR₁₇R₁₈,C═NR₁₉; R₁₆ is H, or C₁-C₄alkyl optionally substituted with OH, ONO,ONO₂; said R₁₇ and R₁₈ are each independently H or C₁-C₄alkyl optionallysubstituted with ONO, ONO₂; said R₁₉ is C₁-C₄alkyl optionallysubstituted with ONO, ONO₂.

In a further preferred embodiment, said R₅ is SO₂NR₁₃R₁₄, wherein R₁₃and R₁₄ together with the nitrogen atom to which they are attached forma mono-cyclic ring selected from imidazol, aziridine, azetidine,pyrrolidine, piperidine, morpholine, piperazine and homopiperazineoptionally substituted with R₁₅; said R₁₅ is C₁-C₄alkyl optionallysubstituted with halogen, OH, ONO₂, C₁-C₃alkoxy, COOR₁₆, NR₁₇R₁₈,C═NR₁₉; R₁₆ is H, or C₁-C₄alkyl optionally substituted with OH, ONO₂;said R₁₇ and R₁₈ are each independently H or C₁-C₄alkyl optionallysubstituted with ONO₂; said R₁₉ is C₁-C₄alkyl optionally substitutedwith ONO₂.

In a further preferred embodiment, said R₅ is SO₂NR₁₃R₁₄, wherein R₁₃and R₁₄ together with the nitrogen atom to which they are attached forma mono-cyclic ring selected from imidazol, pyrrolidine, piperidine,morpholine, piperazine and homopiperazine optionally substituted withR₁₅; said R₁₅ is C₁-C₄alkyl optionally substituted with OH, ONO₂,C₁-C₃alkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉; R₁₆ is H, or C₁-C₄alkyl optionallysubstituted with OH, ONO₂; said R₁₇ and R₁₈ are each independently H orC₁-C₄alkyl optionally substituted with ONO₂; said R₁₉ is C₁-C₄alkyloptionally substituted with ONO₂.

In a further very preferred embodiment, said R₅ is SO₂NR₁₃R₁₄, whereinR₁₃ and R₁₄ together with the nitrogen atom to which they are attachedform a mono-cyclic ring selected from piperidine, and piperazineoptionally substituted with R₁₅; said R₁₅ is C₁-C₃alkyl optionallysubstituted with OH or ONO₂.

In a further preferred embodiment, said X represents a bond orC₁-C₃alkylene optionally substituted with OH. In a further verypreferred embodiment, said X represents a bond or C₁-C₂alkyleneoptionally substituted with OH. In another very preferred embodiment,said X represents a bond. In another very preferred embodiment, said Xrepresents C₁-C₂alkylene optionally substituted with OH.

In a further preferred embodiment, said R₂ is H, OH, C(O)OH,C(O)OC₁-C₃alkyl, CHO, CN, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl, CH═N—OR₉, wherein R₉ isH, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH,COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl.

In a further preferred embodiment, said R₂ is H, OH, C(O)OH,C(O)OC₁-C₃alkyl, CHO, CN, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl, CH═N—OR₉, wherein R₇ isH, C₁-C₃alkyl; and wherein R₉ is H, C₁-C₃alkyl optionally substitutedwith OH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H,OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇,S(O₀₋₂)C₁-C₃alkyl.

In a further preferred embodiment, said R₂ is C(O)OH, C(O)OC₁-C₃alkyl,CHO, CN, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇,S(O₀₋₂)C₁-C₃alkyl, CH═N—OR₉, wherein R₇ is H, C₁-C₃alkyl; and wherein R₉is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH,COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl.

In a further preferred embodiment, said R₂ is C(O)OH, C(O)OC₁-C₃alkyl,CHO, CN, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇,S(O₀₋₂)C₁-C₃alkyl, CH═N—OR₉, wherein R₇ is H, C₁-C₃alkyl; and wherein R₉is H, C₁-C₃alkyl substituted with OH, ONO, ONO₂, CN, COOH,COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl.

In a further very preferred embodiment, said R₂ is CHO, CN, CH═N—OR₉,preferably (E)-CH═N—OR₉, wherein R₉ is H, C₁-C₃alkyl optionallysubstituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, OC(O)H,OC(O)—C₁-C₃alkyl.

In a further very preferred embodiment, said R₂ is CHO, CN, CH═N—OR₉,preferably (E)-CH═N—OR₉, wherein R₉ is H, C₁-C₃alkyl substituted withOH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, OC(O)H, OC(O)—C₁-C₃alkyl.

In a further very preferred embodiment, said R₂ is CH═N—OR₉, preferably(E)-CH═N—OR₉, wherein R₉ is H, C₁-C₃alkyl optionally substituted withOH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H,OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇,S(O₀₋₂)C₁-C₃alkyl.

In a further very preferred embodiment, said R₂ is CH═N—OR₉, preferably(E)-CH═N—OR₉, wherein R₉ is H, C₁-C₃alkyl optionally substituted withOH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, OC(O)H, OC(O)—C₁-C₃alkyl.

In a further very preferred embodiment, said X—R₂ representsC₁-C₃alkylene optionally substituted with OH, ONO, ONO₂, CN, C(O)OH,C₁-C₂alkoxy, C(O)OC₁-C₃alkyl, C(O)N(R₆)OR₇, CHO, OC(O)H,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)N(R₆)OR₇, OC(O)—C₁-C₃alkyl,C(O)N(R₆)OR₇, CR₈═N—OR₉; C(O)OC₁-C₃alkyl, CHO, C(O)N(R₆)OR₇,S(O₀₋₂)C₁-C₃alkyl, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂ or CR₈═N—ONO₂,wherein further preferably, said R₆ is H or CH₃, and said R₈ is H orCH₃.

In a further very preferred embodiment, said X—R₂ representsC₁-C₃alkylene substituted with OH, ONO, ONO₂, CN, C(O)OH, C₁-C₂alkoxy,C(O)OC₁-C₃alkyl, C(O)N(R₆)OR₇, CHO, OC(O)H, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)N(R₆)OR₇, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, CR₈═N—OR₉;C(O)OC₁-C₃alkyl, CHO, C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl, CR₈═N—OR₉,CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂ or CR₈═N—ONO₂, wherein further preferably, saidR₆ is H or CH₃, and said R₈ is H or CH₃.

In a further preferred embodiment, R₇ is H, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkyl substituted with phenyl, benzyl or a heterocyclic ringselected from aziridine, azetidine, pyrollidine, piperidine, morpholine,piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and3,7-diazabicyclo[3,3,0]octane, wherein said phenyl, benzyl or saidheterocyclic ring are independently optionally substituted byC₁-C₃alkyl, F. In a further preferred embodiment, R₇ is H, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃alkyl substituted with phenyl, benzyl or aheterocyclic ring selected from pyrollidine, piperidine, morpholine,piperazine, homopiperazine, wherein said phenyl, benzyl or saidheterocyclic ring are independently optionally substituted byC₁-C₃alkyl.

In a further preferred embodiment, said R₉ is H, C₁-C₃alkyl substitutedwith OH, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl,C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl. In a further preferredembodiment, said R₉ is H, C₁-C₃alkyl substituted with OH, CN, COOH,COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇.

In a further preferred embodiment, said R₁₀ and R₁₁ are eachindependently H, C₁-C₃alkyl optionally substituted with OH, CN, COOH,COOC₁-C₃, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl; or together with thenitrogen atom to which they are attached form a heterocyclic ring,wherein preferably said heterocyclic ring is selected from aziridine,azetidine, pyrollidine, piperidine, morpholine, piperazine andhomopiperazine, wherein said heterocyclic ring is optionally substitutedwith C₁-C₃ alkyl. In a further preferred embodiment, said R₁₀ and R₁₁are each independently H, C₁-C₃alkyl optionally substituted with OH, CN,COOH, COOC₁-C₃, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl; or together with thenitrogen atom to which they are attached form a heterocyclic ring,wherein preferably said heterocyclic ring is selected from pyrollidine,piperidine, morpholine, piperazine and homopiperazine, wherein saidheterocyclic ring is optionally substituted with C₁-C₃ alkyl.

In a further very preferred embodiment, said X—R₂ representsC₁-C₃alkylene substituted with CN, C(O)OH, C(O)OC₁-C₃alkyl,C(O)N(R₆)OR₇, CHO, OC(O)H, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)N(R₆)OR₇, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, CR₈═N—OR₉;C(O)OC₁-C₃alkyl, CHO, C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl, CR₈═N—OR₉,CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂ or CR₈═N—ONO₂, wherein further preferably, saidR₆ is H or CH₃; said R₇ is H, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylsubstituted with phenyl, benzyl or a heterocyclic ring selected frompyrollidine, piperidine, morpholine, piperazine, homopiperazine, whereinsaid phenyl, benzyl or said heterocyclic ring are independentlyoptionally substituted by C₁-C₃alkyl; said R₈ is H or CH₃; said R₉ is H,C₁-C₃alkyl substituted with OH, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy,OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇.

In a further very preferred embodiment, said X—R₂ representsC₁-C₃alkylene substituted with CN, C(O)OH, C(O)OC₁-C₃alkyl,C(O)N(R₆)OR₇, CHO, OC(O)H, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)N(R₆)OR₇, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, CR₈═N—OR₉;C(O)OC₁-C₃alkyl, CHO, C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl, CR₈═N—OR₉,CR₈═N—NR₁₀R₁₁, wherein further preferably, said R₆ is H or CH₃; said R₇is H, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkyl substituted with phenyl,benzyl or a heterocyclic ring selected from pyrollidine, piperidine,morpholine, piperazine, homopiperazine, wherein said phenyl, benzyl orsaid heterocyclic ring are independently optionally substituted byC₁-C₃alkyl; said R₈ is H or CH₃; said R₉ is H, C₁-C₃alkyl substitutedwith OH, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl,C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇; said R₁₀ and R₁₁ are each independently H,C₁-C₃alkyl optionally substituted with OH, CN, COOH, COOC₁-C₃,C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl; or together with thenitrogen atom to which they are attached form a heterocyclic ring,wherein preferably said heterocyclic ring is selected from pyrollidine,piperidine, morpholine, piperazine and homopiperazine, wherein saidheterocyclic ring is optionally substituted with C₁-C₃ alkyl.

In a further very preferred embodiment, said X—R₂ representsC₁-C₃alkylene substituted with CN, C(O)OH, C(O)OC₁-C₃alkyl,C(O)N(R₆)OR₇, CHO, OC(O)H, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)N(R₆)OR₇, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, CR₈═N—OR₉;C(O)OC₁-C₃alkyl, CHO, C(O)N(R₆)OR₇, CR₈═N—OR₉, wherein furtherpreferably, said R₆ is H or CH₃; said R₇ is H, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkyl substituted with phenyl, benzyl or a heterocyclic ringselected from pyrollidine, piperidine, morpholine, piperazine,homopiperazine, wherein said phenyl, benzyl or said heterocyclic ringare independently optionally substituted by C₁-C₃alkyl; said R₈ is H orCH₃; said R₉ is H, C₁-C₃alkyl substituted with OH, CN, COOH,COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇.

In a further very preferred embodiment, said X—R₂ represents CR₈═N—OR₉,preferably (E)-CR₈═N—OR₉, wherein said R₈ is H or CH₃, preferablywherein said R₈ is H, and wherein said R₉ is H or C₁-C₃ alkyl optionallysubstituted with OH or C₁-C₃ alkyl optionally substituted with OH.

In a further very preferred embodiment, said X—R₂ represents CH═N—OR₉,preferably (E)-CH═N—OR₉, wherein said R₉ is H or C₁-C₃ alkyl optionallysubstituted with OH or CN, and wherein preferably said R₉ is H or C₁-C₃alkyl substituted with OH or CN; and wherein further preferably said R₉is H or C₁-C₃ alkyl substituted with OH.

Without being bound this theory, it is believed that thefunctionalization of the group R₂ and thus the group X—R₂, allows anincreased interaction with the PDE5 enzyme and thus an increasedinhibition effect. In particular, R₂ with an oxime functionality, andhereby in particular with a trans-geometry of the oxime functionalityhas been found to be highly beneficial.

In a further preferred embodiment, said R₁ is C₁-C₃ alkyl; said R₂ isCH═N—OR₉, preferably (E)-CH═N—OR₉, wherein said R₉ is H or C₁-C₃ alkyloptionally substituted with OH or C₁-C₃ alkyl optionally substitutedwith OH; R₃ is C₁-C₆ alkyl; said R₄ is C₁-C₆ alkoxy; said R₅ isSO₂NR₁₃R₁₄ wherein R₁₃ and R₁₄ are each independently H or together withthe nitrogen atom to which they are attached form a mono-cyclic ringselected from imidazol, aziridine, azetidine, pyrrolidine, piperidine,morpholine, piperazine and homopiperazine optionally substituted withR₁₅; wherein said R₁₅ is C₁-C₄alkyl optionally substituted with halogen,OH, ONO, ONO₂, C₁-C₃alkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉; R₁₆ is H, orC₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂; said R₁₇ andR₁₈ are each independently H or C₁-C₄alkyl optionally substituted withONO, ONO₂; said R₁₉ is C₁-C₄alkyl optionally substituted with F, ONO,ONO₂.

In a further preferred embodiment, said R₁ is C₁-C₃ alkyl; said R₂ isCH═N—OR₉, preferably (E)-CH═N—OR₉, wherein said R₉ is H or C₁-C₃ alkyloptionally substituted with OH or CN; R₃ is C₁-C₆ alkyl; said R₄ isC₁-C₆ alkoxy; said R₅ is SO₂NR₁₃R₁₄ wherein R₁₃ and R₁₄ are eachindependently H or together with the nitrogen atom to which they areattached form a mono-cyclic ring selected from imidazol, aziridine,azetidine, pyrrolidine, piperidine, morpholine, piperazine andhomopiperazine optionally substituted with R₁₅; wherein said R₁₅ isC₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂,C₁-C₃alkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉; R₁₆ is H, or C₁-C₄alkyl optionallysubstituted with F, OH, ONO, ONO₂; said R₁₇ and R₁₈ are eachindependently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂;said R₁₉ is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂.

Further very preferred embodiments of the present invention arerepresented by individual compounds of formula I or pharmaceuticallyacceptable salts, solvates or hydrates thereof.

Thus, in another very preferred embodiment, said compound of formula Iis selected from

-   (E)-2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde    oxime

-   2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-6-(hydroxymethyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

-   (2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl    acetate

-   2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylic    acid

-   N-(benzyloxy)-2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

-   Methyl    2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

-   2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-N-hydroxy-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

-   2-((2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)methoxy)acetic    acid

-   2-((2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)methoxy)-N-hydroxy-N-methylacetamide

-   2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde

-   6-(1,3-dihydroxypropyl)-2-(2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonyl)    phenyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

-   5-methyl-2-(5-(4-methylpiperazin-1-yl)sulfonyl)-2-propoxyphenyl)-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde

-   2-(5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde

-   2-(5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)-2-propoxyphenyl)-6-(hydroxymethyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

-   (E)-5-methyl-2-(5-((4-methylpiperazin-1-yl)sulfonyl)-2-propoxyphenyl)-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde    O-methyl oxime

-   2-(5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde

-   2-(1-((3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl    nitrate

-   (E)-2-(5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde    oxime

-   ethyl-3-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-hydroxypropanoate

-   3-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-N,3-dihydroxypropanamide

-   3-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-hydroxypropanenitrile

-   (E)-2-(1-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl    nitrate

-   2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde

-   (E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde    oxime

-   2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde    O-methyloxime

-   (E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde    O-(2-hydroxyethyl) oxime

-   2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde

-   (E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde    oxime

-   (E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde    O-methyl oxime

-   (E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde    O-(2-hydroxyethyl) oxime

-   2-(4-((4-ethoxy-3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl    nitrate

-   (E)-2-(4-((4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl    nitrate

-   2-(4-((4-ethoxy-3-(5-ethyl-6-formyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl    nitrate

-   (E)-2-(4-((4-ethoxy-3-(5-ethyl-6-((hydroxyimino)methyl)-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl    nitrate

-   (E)-2-(4-((4-ethoxy-3-(6-((m    ethoxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl    nitrate

-   (E)-2-(4-((4-ethoxy-3-(6-(((2-hydroxyethoxy)imino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl    nitrate

-   (E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde    oxime

-   (E)-2-(1-((4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethyl    nitrate

-   (E)-2-(2-ethoxy-5-((4-(3-hydroxypropyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde    oxime

-   (E)-3-(4-((4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)propyl    nitrate

-   2-(2-ethoxy-5-((4-(3-hydroxypropyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

-   (Z)-2-(1-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl    nitrate

In another very preferred embodiment, said compound of formula I isselected from

-   (E)-2-(5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde    oxime (10; and-   (E)-2-(1-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl    nitrate (1v).

In another very preferred embodiment, said compound of formula I is(E)-2-(5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (10.

In another very preferred embodiment, said compound of formula I is(E)-2-(1-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethylnitrate (1v).

In another very preferred embodiment, said compound of formula I is(E)-2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1a).

In another very preferred embodiment, said compound of formula I is(E)-5-methyl-2-(5-((4-methylpiperazin-1-yl)sulfonyl)-2-propoxyphenyl)-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-methyl oxime (1o).

In another very preferred embodiment, said compound of formula I is(E)-2-(5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1r).

In another very preferred embodiment, said compound of formula I isethyl-3-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-hydroxypropanoate(1s).

In another very preferred embodiment, said compound of formula I is3-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-N,3-dihydroxypropanamide(10.

In another very preferred embodiment, said compound of formula I is3-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-hydroxypropanenitrile(1u).

In another very preferred embodiment, said compound of formula I is2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1w).

In another very preferred embodiment, said compound of formula I is(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-(2-hydroxyethyl) oxime (1z).

In another very preferred embodiment, said compound of formula I is(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1ab).

In another very preferred embodiment, said compound of formula I is(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-(2-hydroxyethyl) oxime (1ad).

In another very preferred embodiment, said compound of formula I is(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-(2-hydroxyethyl) oxime (1ad).

In another very preferred embodiment, said compound of formula I is2-(4-((4-ethoxy-3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ae).

In another very preferred embodiment, said compound of formula I is(E)-2-(4-((4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1af).

In another very preferred embodiment, said compound of formula I is(E)-2-(4-((4-ethoxy-3-(5-ethyl-6-((hydroxyimino)methyl)-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ah).

In another very preferred embodiment, said compound of formula I is(E)-2-(4-((4-ethoxy-3-(6-(((2-hydroxyethoxy)imino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ak).

In another very preferred embodiment, said compound of formula I is(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (I al).

In another very preferred embodiment, said compound of formula I is(E)-2-(1-((4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethylnitrate (1am).

In another very preferred embodiment, said compound of formula I is(E)-2-(2-ethoxy-5-((4-(3-hydroxypropyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1an).

In another very preferred embodiment, said compound of formula I is(E)-3-(4-((4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)propylnitrate (1ao).

It has been shown that compounds of the present invention are potent andselective inhibitors of cGMP specific PDE. Furthermore, it has beenfound that the compounds of the present invention can be tailored tobecome dual-pharmacology NO-releasing PDE5 inhibitors which are believedto release NO in addition to its PDE 5 inhibition in a more thanadditive fashion. Thus, compounds of formula I are of interest for usein therapy, specifically for the treatment of a variety of conditionswhere inhibition of cGMP specific PDE is thought to be beneficial.

Thus, in a further aspect, the present invention provides for apharmaceutical composition comprising at least one of the inventivecompound of formula I, or a pharmaceutically acceptable salt, solvate orhydrate thereof, and a pharmaceutically acceptable excipient, adjuvant,or carrier. In another aspect, the present invention provides for apharmaceutical composition comprising exactly one inventive compound offormula I, or a pharmaceutically acceptable salt, solvate or hydratethereof, and a pharmaceutically acceptable excipient, adjuvant, orcarrier. Pharmaceutically acceptable excipient, adjuvant, or carrier areknown to the skilled person in the art.

In another aspect, the present invention provides for a compound offormula I, or a pharmaceutically acceptable salt, solvate or hydratethereof, for use as a pharmaceutical. In again another aspect, thepresent invention provides for a compound of formula I, or apharmaceutically acceptable salt, solvate or hydrate thereof, for use asan animal medicament.

It has surprisingly been found that the compounds of the presentinvention are very potent and selective inhibitors of PDE5. Furthermore,we have surprisingly found that the compounds of the present inventioncan be tailored to become dual-pharmacology NO-releasing PDE5 inhibitorswhich are believed to release NO in addition to its PDE 5 inhibition ina more than additive fashion. Moreover, it has surprisingly been foundthat preferred compounds of the present invention show even asignificantly higher PDE5 inhibition activity as compared to known PDE5inhibitors such as sildenafil. As a consequence, the novel pyrrolotriazine compounds of the present invention are useful in the therapyand prophylaxis of diseases which are associated with a disturbed cGMPbalance. In particular, the compounds of the present invention arepotent and selective inhibitors of cyclic guanosine 3′-5′-monophosphatespecific phosphodiesterase 5 (cGMP specific PDE5) and thus have utilityin variety of therapeutic areas where such inhibition is thought to bebeneficial. Some of the preferred therapeutic areas are wound healing,in particular chronic wound healing, diabetic foot, diabetic foot ulcer,leg ulcer, Raynaud's, male erectile dysfunction, female sexualdysfunction, Alzheimer's disease, diabetes, hair loss, skin aging,vascular aging, pulmonary artery hypertension and chronic heart failure.

As a consequence of the selective PDE5 inhibition exhibited by compoundsof the present invention, cGMP levels are expected to be elevated, whichin turn can give rise to beneficial anti-platelet, anti-vasospastic,vasodilatory, natriuretic and diuretic activities as well aspotentiation of the effects of endothelium-derived relaxing factor(EDRF) nitric oxide (NO), nitrovasodilators, atrial natriuretic factor(ANF), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP)and endothelium-dependent relaxing agents such as bradykinin,acetylcholine and 5-HT1. The compounds of formula I therefore haveutility in the treatment of a number of disorders, including stable,unstable and variant (Prinzmetal) angina, hypertension, pulmonaryhypertension, congestive heart failure, renal failure, atherosclerosis,conditions of reduced blood vessel patency (e.g. post-percutaneoustransluminal coronary angioplasty), peripheral vascular disease,vascular disorders such as Raynaud's disease, inflammatory diseases,stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis,diabetes, glaucoma and diseases characterized by disorders of gutmotility like irritable bowel syndrome, wound healing, in particularchronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer,Alzheimer's disease, hair loss, skin aging, vascular aging, pulmonaryartery hypertension and chronic heart failure.

Thus, in another aspect, the present invention provides for a compoundof formula I, or a pharmaceutical composition, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, for use in a method oftreating or preventing a disease alleviated by inhibition of PDE-5 in ahuman or in a non-human mammal, preferably in a human. Preferably, saiddisease is selected from wound healing, chronic wound healing, diabeticfoot ulcer, leg ulcer, Raynaud's disease, male erectile dysfunction,female sexual dysfunction, hair loss, skin aging, vascular aging,pulmonary artery hypertension; stable, unstable and variant (Prinzmetal)angina; hypertension, pulmonary hypertension, chronic obstructivepulmonary disease, congestive heart failure, renal failure,atherosclerosis, conditions of reduced blood vessel patency, peripheralvascular disease, vascular disorders, systemic sclerosis (SSc),scleroderma, morphea, inflammatory diseases, stroke, bronchitis, chronicasthma, allergic asthma, allergic rhinitis, diabetic neuropathy,Idiopathic pulmonary fibrosis (IPF), peyronic's disease, diabetes,glaucoma or a disease characterized by disorders of gut motility likeirritable bowel syndrome, liver fibrosis, Alzheimer's disease andchronic heart failure, wherein further preferably said disease isselected from wound healing, chronic wound healing, diabetic foot ulcer,leg ulcer, diabetic neuropathy, peripheral vascular disease, vasculardisorders, Raynaud's disease, systemic sclerosis (SSc), scleroderma,pulmonary artery hypertension, diabetes, male erectile dysfunction, andwherein again further preferably said disease is selected from woundhealing, chronic wound healing, diabetic foot ulcer, leg ulcer anddiabetic neuropathy.

In again another aspect, the present invention provides for a compoundof formula I, or a pharmaceutical composition, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, for use in a method oftreating or preventing a disease by inhibition of PDE-5 in a human or ina non-human mammal, preferably in a human. In again another aspect, thepresent invention provides for a compound of formula I, or apharmaceutical composition, or a pharmaceutically acceptable salt,solvate or hydrate thereof, for use in a method of treating a medicalcondition in a human or in a non-human mammal, preferably in a human,wherein for said medical condition inhibition of PDE5 is desired.

In again another aspect, the present invention provides use of acompound of formula I, or a pharmaceutical composition, or apharmaceutically acceptable salt, solvate or hydrate thereof, for themanufacture of a medicament for the treatment or prevention of a diseaseby inhibition of PDE-5 in a human or in a non-human mammal, preferablyin a human. In again another aspect, the present invention provides useof a compound of formula t, or a pharmaceutical composition, or apharmaceutically acceptable salt, solvate or hydrate thereof, for themanufacture of a medicament for the treatment or prevention of a diseasealleviated by inhibition of PDE-5 in a human or in a non-human mammal,preferably in a human. In again another aspect, the present inventionprovides use of a compound of formula I, or a pharmaceuticalcomposition, or a pharmaceutically acceptable salt, solvate or hydratethereof, for the manufacture of a medicament for the treatment a medicalcondition in a human or in a non-human mammal, preferably in a human,wherein for said medical condition inhibition of PDE5 is desired.

In again another aspect, the present invention provides for a method oftreating or preventing a disease by inhibition of PDE-5 in a human or ina non-human mammal, preferably in a human, comprising administering tosaid human or said non-human mammal, preferably to said human aneffective amount of a compound of formula L or a pharmaceuticalcomposition, or a pharmaceutically acceptable salt, solvate or hydratethereof. In again another aspect, the present invention provides for amethod of treating or preventing a disease alleviated by inhibition ofPDE-5 in a human or in a non-human mammal, preferably in a human,comprising administering to said human or said non-human mammal,preferably to said human an effective amount of a compound of formula I,or a pharmaceutical composition, or a pharmaceutically acceptable salt,solvate or hydrate thereof. In again another aspect, the presentinvention provides for a method of treating a medical condition in ahuman or in a non-human mammal, preferably in a human, wherein for saidmedical condition inhibition of PDE5 is desired, comprisingadministering to said human or said non-human mammal, preferably to saidhuman an effective amount of a compound of formula I, or apharmaceutical composition, or a pharmaceutically acceptable salt,solvate or hydrate thereof.

In a preferred embodiment of the present invention, said disease or saida medical condition is selected from wound healing, preferably chronicwound healing, diabetic foot, diabetic foot ulcer, leg ulcer, Raynaud'sdisease, male erectile dysfunction, female sexual dysfunction, diabetes,hair loss, skin aging, vascular aging, pulmonary artery hypertension;stable, unstable, and variant (Prinzmetal) angina; hypertension,pulmonary hypertension, chronic obstructive pulmonary disease,congestive heart failure, renal failure, atherosclerosis, conditions ofreduced blood vessel patency, peripheral vascular disease, vasculardisorders, systemic sclerosis (SSc), scleroderma, morphea, inflammatorydiseases, stroke, bronchitis, chronic asthma, allergic asthma, allergicrhinitis, diabetic neuropathy, Idiopathic pulmonary fibrosis (IPF),peyronic's disease, glaucoma or a disease characterized by disorders ofgut motility like irritable bowel syndrome, liver fibrosis, Alzheimer'sdisease and chronic heart failure, wherein preferably said disease isselected from wound healing, preferably chronic wound healing, diabeticfoot, diabetic foot ulcer, leg ulcer, diabetic neuropathy, peripheralvascular disease, vascular disorders such as Raynaud's disease, systemicsclerosis (SSc), scleroderma, pulmonary artery hypertension, diabetes,male erectile dysfunction, and wherein again further preferably saiddisease is selected from wound healing, preferably chronic woundhealing, diabetic foot, diabetic foot ulcer, leg ulcer and diabeticneuropathy.

There is thus provided as a further aspect of the present invention acompound of formula I for use in the treatment of wound healing,preferably chronic wound healing, diabetic foot, diabetic foot ulcer,leg ulcer, Raynaud's disease, male erectile dysfunction, female sexualdysfunction, diabetes, hair loss, skin aging, vascular aging, pulmonaryartery hypertension; stable, unstable, and variant (Prinzmetal) angina;hypertension, pulmonary hypertension, chronic obstructive pulmonarydisease, congestive heart failure, renal failure, atherosclerosis,conditions of reduced blood vessel patency, peripheral vascular disease,vascular disorders, systemic sclerosis (SSc), scleroderma, morphea,inflammatory diseases, stroke, bronchitis, chronic asthma, allergicasthma, allergic rhinitis, diabetic neuropathy, Idiopathic pulmonaryfibrosis (IPF), peyronic's disease, glaucoma or a disease characterizedby disorders of gut motility like irritable bowel syndrome, liverfibrosis, Alzheimer's disease and chronic heart failure, whereinpreferably said disease is selected from wound healing, preferablychronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer,diabetic neuropathy, peripheral vascular disease, vascular disorderssuch as Raynaud's disease, systemic sclerosis (SSc), scleroderma,pulmonary artery hypertension, diabetes, male erectile dysfunction, andwherein again further preferably said disease is selected from woundhealing, preferably chronic wound healing, diabetic foot, diabetic footulcer, leg ulcer and diabetic neuropathy.

According to another aspect of the invention, there is provided the useof a compound of formula I for the manufacture of a medicament for thetreatment of wound healing, preferably chronic wound healing, diabeticfoot, diabetic foot ulcer, leg ulcer, Raynaud's disease, male erectiledysfunction, female sexual dysfunction, diabetes, hair loss, skin aging,vascular aging, pulmonary artery hypertension; stable, unstable, andvariant (Prinzmetal) angina; hypertension, pulmonary hypertension,chronic obstructive pulmonary disease, congestive heart failure, renalfailure, atherosclerosis, conditions of reduced blood vessel patency,peripheral vascular disease, vascular disorders, systemic sclerosis(SSc), scleroderma, morphea, inflammatory diseases, stroke, bronchitis,chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy,Idiopathic pulmonary fibrosis (IPF), peyronic's disease, glaucoma or adisease characterized by disorders of gut motility like irritable bowelsyndrome, liver fibrosis, Alzheimer's disease and chronic heart failure,wherein preferably said disease is selected from wound healing,preferably chronic wound healing, diabetic foot, diabetic foot ulcer,leg ulcer, diabetic neuropathy, peripheral vascular disease, vasculardisorders such as Raynaud's disease, systemic sclerosis (SSc),scleroderma, pulmonary artery hypertension, diabetes, male erectiledysfunction, and wherein again further preferably said disease isselected from wound healing, preferably chronic wound healing, diabeticfoot, diabetic foot ulcer, leg ulcer and diabetic neuropathy.

In a further aspect, the invention provides a method of treating woundhealing, preferably chronic wound healing, diabetic foot, diabetic footulcer, leg ulcer, Raynaud's disease, male erectile dysfunction, femalesexual dysfunction, diabetes, hair loss, skin aging, vascular aging,pulmonary artery hypertension; stable, unstable, and variant(Prinzmetal) angina; hypertension, pulmonary hypertension, chronicobstructive pulmonary disease, congestive heart failure, renal failure,atherosclerosis, conditions of reduced blood vessel patency, peripheralvascular disease, vascular disorders, systemic sclerosis (SSc),scleroderma, morphea, inflammatory diseases, stroke, bronchitis, chronicasthma, allergic asthma, allergic rhinitis, diabetic neuropathy,Idiopathic pulmonary fibrosis (IPF), peyronic's disease, glaucoma or adisease characterized by disorders of gut motility like irritable bowelsyndrome, liver fibrosis, Alzheimer's disease and chronic heart failure,wherein preferably said disease is selected from wound healing,preferably chronic wound healing, diabetic foot, diabetic foot ulcer,leg ulcer, diabetic neuropathy, peripheral vascular disease, vasculardisorders such as Raynaud's disease, systemic sclerosis (SSc),scleroderma, pulmonary artery hypertension, diabetes, male erectiledysfunction, and wherein again further preferably said disease isselected from wound healing, preferably chronic wound healing, diabeticfoot, diabetic foot ulcer, leg ulcer and diabetic neuropathy in a humanor in non-human mammal, preferably in a human, said method comprisesadministering to said human or said non-human mammal, preferably to saidhuman, an effective amount of a compound of formula I.

In a very preferred embodiment of the present invention, said disease orsaid a medical condition is selected from wound healing, preferablychronic wound healing, diabetic foot, diabetic foot ulcer and leg ulcer.

Chronic, non-healing skin wounds such as in diabetes mellitus aregoverned by complex disease mechanisms including impaired angiogenesis,defective microcirculation, and endothelial dysfunction. Diabetic footulcer and chronic wounds are a major source of morbidity and is aleading cause of hospitalizations in diabetic patients. It afflicts 15%of diabetes patients (275 Mio) and is a huge burden to patients andpayers (12 billion $/year). 3-4% of all diabetic patients will get lowerlimb amputations every year. Ultra-potent PDE5 inhibitors or compoundsintegrating highly potent inhibition of PDE5 and activation of nitricoxide dependent soluble guanylate cyclase as the ones of the presentinvention can be expected to accelerate wound healing.

As used herein, the terms “treatment”, “treat”, “treated” or “treating”refer to prophylaxis and/or therapy. In one embodiment, the terms“treatment”, “treat”, “treated” or “treating” refer to a therapeutictreatment. In another embodiment, the terms “treatment”, “treat”,“treated” or “treating” refer to a prophylactic treatment. Preferably,beneficial or desired clinical results of said treatment include, butare not limited to, alleviation of symptoms, diminishment of extent ofdisease or medical condition, stabilized (i.e., not worsening) state ofdisease or medical condition, delay or slowing of disease or medicalcondition progression, amelioration or palliation of the disease ormedical condition state.

As used herein, the term “effective amount” refers to an amountnecessary or sufficient to realize a desired biologic effect.Preferably, the term “effective amount” refers to an amount of acompound of formula I of the present invention that (i) treats orprevents the particular disease, medical condition, or disorder, (ii)attenuates, ameliorates, or eliminates one or more symptoms of theparticular disease, medical condition, or disorder, or (iii) prevents ordelays the onset of one or more symptoms of the particular disease,medical condition, or disorder described herein. An effective amount ofthe inventive compound of formula I, or said pharmaceutical composition,would be the amount that achieves this selected result, and such anamount could be determined as a matter of routine by a person skilled inthe art. Further preferably, the term “effective amount”, as usedherein, refers to an amount necessary or sufficient to be effective toincrease the inhibition of PDE5, typically and preferably as determinedin Example 64, or to increase the formation of cGMP, typically andpreferably as determined in Example 65. The effective amount can varydepending on the particular composition being administered and the sizeof the subject. One of ordinary skill in the art can empiricallydetermine the effective amount of a particular composition of thepresent invention without necessitating undue experimentation.

The term “mammal”, as used herein, includes, but is not limited to,humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows,pigs, and sheep. The term “mammal”, as used herein, preferably refers tohumans.

The compounds of formula I and the pharmaceutical compositions of thepresent invention may be administered by any suitable route, for exampleby oral, buccal, sub-lingual, rectal, vaginal, nasal, topical orparenteral administration, which forms another aspects of the presentinvention.

In again another aspect, the present invention provides for a compoundof the formula II:

wherein R₁, R₂, R₃ are defined as for the compound of formula I.

In still a further aspect, the present invention provides for a compoundof formula IV

wherein X, R₁, R₂, R₃, R₄, R₅ are defined as for the compound of formulaI.

In again another aspect, the present invention provides for a processfor the preparation of a compound of formula I,

wherein said process comprises:

-   -   (a) reaction of a compound of formula II with a benzoic acid        derivative of formula III in an aprotic or a protic solvent to        generate a compound of formula IV

-   -   (b) cyclization of said compound of formula IV to yield compound        of formula I,        wherein X, R₁, R₂, R₃, R₄, and R₅ are defined as for the        compound of formula I.

In again another aspect, the present invention provides for a processfor the preparation of a compound of formula I, wherein said processcomprises

-   -   (a) reaction of a compound of formula VI with a benzoyl chloride        derivative of formula VIA to generate a compound of formula VII

-   -   (b) hydrolysis of the ester compound of formula VII to an acid        derivative of formula VIII

-   -   (c) amination of said compound of formula VIII to yield a        compound of formula IV

-   -   (d) cyclization of said compound of formula IV to yield compound        of formula I,        wherein X, R₁, R₂, R₃, R₄, and R₅ are defined as for the        compound of formula I; and        wherein R′ is C₁-C₄ alkyl, benzyl, 4-alkoxybenzyl.

In again another aspect, the present invention provides for a processfor the preparation of a compound of formula I, wherein said processcomprises conversion of compound of formula IA to yield compound offormula I

wherein X, R₁, R₂, R₃, R₄, and R₅ are defined as for the compound ofform I in any one of the claims 1 to 8.

Compounds of formula I may be prepared by the following reaction SCHEME1 and reaction SCHEME 2. These schemes represent the synthesis ofgeneric compounds of formula I and forms part of the present invention.

Thus, a process for preparing compounds of formula I involves synthesisof intermediate II which is a precursor to compound of formula IV whichacts as a precursor to other compounds of formula I. Compound of formulaIV is synthesized alternatively as shown in SCHEME 2, starting fromcompound of formula V, which is subsequently converted to compound offormula VI, followed by compound VII and VIII; SCHEME 2 thus forms analternate route for the synthesis of the inventive compound of formulaI.

Compound of formula II is reacted with a benzoic acid derivative offormula III in an aprotic or a protic solvent, selected from the groupcomprising DMF, acetonitrile, dialkylether, chlorinated hydrocarbons.The reaction is performed in the presence of a condensation reagent likee.g. thionyl chloride, phosphoroxy chloride, carbodiimide reagents likeDCC, EDC or DCI, HBTU in presence or absence of bases to generate acompound of formula IV, which undergoes a reductive cyclization in thepresence of bases like potassiumhydroxide, potassium tert-butoxide insolvents like butanol, poly-ethyleneglycol, DMF to generate compound offormula IA. Compound IA under various reaction conditions is convertedto compounds of the type I.

Wherein R′ typically and preferably comprises: C₁-C₄ alkyl, benzyl,4-alkoxybenzyl. The above alternate reaction sequence can beschematically represented as follows, wherein the substitutions R′ is asdefined above and R₁ is typically and preferably methyl, R₂ is typicallyand preferably formyl; R₃ is typically and preferably propyl, R₄ istypically and preferably propoxy, R₅ is typically and preferablyhydrogen.

For the conversion of compound of formula V to VI, any amination reagentcan be employed like NH₄OH/NaOCl or the like. The reaction is performedin the presence of a base optionally under phase transfer conditionsusing phase transfer catalyst. The base that can be employed is NaOH,KOH, potassium tert-butoxide or the like. The phase transfer catalystthat can be employed for this purpose are benzyltrimethylammoniumchloride, benzyltriethylammonium chloride, methyltricaprylammoniumchloride, methyltributylammonium chloride, and methyltrioctylammoniumchloride or the like. The reaction is performed in the presence of waterand a another solvent which is typically and preferably selected fromchlorinated hydrocarbon solvents like dichloromethane, 1,2dichloroethane, ether solvents like diethyl ether, tertiary butyl etheror the like; The reaction is preferably performed at temperaturesranging from between −20 to 30° C.

The thus obtained aminated product of the formula VI is reacted with asuitable activated benzoic acid compounds, preferably benzoic acidchloride. The reaction is performed in the presence of suitable amines,tertiary amine like diisopropylethylamine being the most preferable. Thereaction is carried out in the presence of aprotic cyclic hydrocarbonsolvent or halo-hydrocarbons wherein toluene and methylene chloridebeing the most preferable. The reaction is typically and preferablyperformed in the temperatures ranging from −20 to 30° C. The estermoiety of the compound of VII is hydrolyzed in the presence of alkalihydroxides like NaOH, LiOH, KOH and the reaction can be performed inwater, alcohols like ethanol, propanol n-butanol or the like, cyclicethers like tetrahydrofuran.

Amination of compound of formula VIII can be carried out by anyamination reagents, wherein any ammonium salt can be employed, NH₄Cl orNH₄OAc being the most preferable. The reaction is performed in thepresence of a condensation reagent like thionyl chloride, phosphoroxychloride, carbodiimide reagents like DCC, EDC or DCI, wherein HBTU beingthe most preferred. The solvents that can be employed are aproticsolvents like amides, ethers and hydrocarbons like dimethylformamide,tetrahydrofuran, methylenechloride. The reaction is typically andpreferably performed at temperatures ranging from −20 to 30° C. The thusobtained compound IV is converted to I by cyclization to the triazine.The cyclization can be carried out in the presence of strong bases likepotassium tert-butoxide. The reaction is preferably carried out in thepresence of solvents like alcohols, wherein the preferred alcoholicsolvent is tertiary butanol or PEG 400 or similar polyether solvents.The temperature of the reaction can range between 120-160° C.

Intermediate II of SCHEME 1, wherein R₂ is formyl is a preferredembodiment of the present invention.

Thus, for example, a specific process for preparing one of the compoundfalling under the group of compounds II, of formula 2a comprisestreating ethyl-3-oxobutanoate with acetic acid/sodium nitrite togenerate an oxime (Z)-ethyl-2-(hydroxyimino)-3-oxobutanoate (5a) bynitrosation of the active methylene group.

Compound 5a on condensation with (E)-hex-2-enal followed by cyclisationyield a pyrrole derivative,ethyl-4-formyl-1-hydroxy-3-methyl-5-propyl-1H-pyrrole-2-carboxylate(6a), which on Zinc/acetic acid reduction yieldethyl-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylate (7a)

Carboxylate compound 7a was derivatized to the corresponding amide 8awhich is subsequently converted to the intermediate 2a,1-amino-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxamide.

Compounds of formula II are preferred intermediates for the synthesis ofcompounds of formula I.

Thus in accordance with the present invention, intermediate II,preferably when R₂=formyl, is subsequently reacted with benzoic acidderivative of the formula III

wherein R₄ and R₅ are as defined above to generate

which is cyclized to a pyrrolo triazine compound

Compound IA is subsequently converted to various compounds of formula I,like 1a, 1b, 1c, 1d, 1e, 1f, 1g by oxidation, reduction, condensation orthe like.

As an example, compound IA, when R₁ is methyl, R₂ is CHO, R₃ is propyl,R₄ is ethoxy, R₅ is SO₂NR₁₀R₁₁, wherein R₁₀R₁₁ together form

represents

Compound 1j is a novel compound and forms yet another part of theinvention

Starting from compound 1j, under various reaction conditions, compounds1a, 1b, 1c, 1d, 1e, 1f, 1g are prepared, as in SCHEME 3 and formsanother part of the present invention.

Thus, compound 1j is oxidized in presence of suitable oxidizing agentslike sodium chlorite, in the presence of solvents like acetonitrile,tetrahydrofurane or tert-butanol to generate compound of formula 1d.Compound 1d is converted to corresponding methyl ester if by treatmentwith methanol and thionyl chloride; 1d on the other hand is converted toan amide derivative 1e which is subsequently converted to a hydroxamicacid 1g.

Compound 1j is converted to an aldoxime of the type 1a which in turngenerated a hydroxymethyl derivative 1b. Compound 1j is subsequentlyconverted into a methylester of the type 1c.

Likewise, compounds 1h and 1i are synthesized starting from 1j.

EXAMPLES

Synthesis of some of the compounds of formula I are exemplified below.The following examples further illustrate the present invention, butshould not be construed in any way as to limit its scope.

Example 1 (Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate (5a)

To a stirring solution of ethyl 3-oxobutanoate (500 mg, 3.84 mmol) inacetic acid (5 mL) was added sodium nitrate (330 mg, 4.50 mmol) in water(10 mL) and the resultant reaction mixture was stirred at RT for 16 h.The reaction mixture was quenched with saturated ammonium chloridesolution and extracted with dichloromethane (2×20 mL). The combineddichloromethane layer was washed with brine and dried over anhydroussodium sulfate and concentrated under reduced pressure to afford thetitle compound as a solid (750 mg). ¹H NMR (300 MHz, CDCl₃) δ=9.09 (brs, 1H), 4.39 (q, J=7.2 Hz, 2H), 2.41 (s, 3H), 1.36 (t, J=7.3 Hz, 3H),Mass (M−H)=158.1.

Example 2 Ethyl4-formyl-1-hydroxy-3-methyl-5-propyl-1H-pyrrole-2-carboxylate (6a)

(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate (5a) (10 g, 62.83 mmol),(E)-hex-2-enal (12.25 g, 125.7 mmol) in toluene, was addeddi-isopropylamine (1.26 g, 12.56 mmol) and the resultant reactionmixture was stirred at RT for 16 h. The reaction mixture was quenchedwith aqueous Ammonium chloride solution (100 mL) and extracted withdichloromethane (2×200 mL). The combined dichloromethane layer waswashed with brine and dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Purification by columnchromatography (100-200 mesh silica gel, 0-5% ethyl acetate in pet etheras eluent) afforded the title compound as a solid (10.5 g). ¹H NMR (400MHz, CDCl₃) δ=12.35 (d, J=1.4 Hz; 1H), 9.95 (d, J=1.4 Hz; 1H), 4.51-4.35(m, 2H), 3.02-2.85 (m, 2H), 2.56 (d, J=1.4 Hz; 3H), 1.77-1.62 (m, 2H),1.43 (dt, J=1.2, 7.1 Hz; 3H), 1.04-0.91 (m, 3H), Mass (M+H)=240.1.

Example 3 Ethyl 4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylate (7a)

To a stirring solution of ethyl4-formyl-1-hydroxy-3-methyl-5-propyl-1H-pyrrole-2-carboxylate (6a) (18g, 75.51 mmol) in dichloromethane (1.8 L), were added zinc dust (34 g,527.1 mmol) and acetic acid (74 mL) and the resultant reaction mixturewas stirred at RT for 30 min. The reaction mixture was quenched withsaturated sodium bicarbonate solution and adjusted PH to 7 thenextracted with dichloromethane (2×250 mL). The combined dichloromethanelayer was washed with brine and dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Purification by columnchromatography (100-200 mesh silica gel, 5% methanol in dichloromethaneas eluent) afforded the title compound as a solid (8 g). [SM wasrecovered by eluting with 5% ethyl acetate in pet ether as eluent]. ¹HNMR (300 MHz, CDCl₃) δ=10.01 (s, 1H), 9.04 (br s, 1H), 4.34 (q, J=7.4Hz, 2H), 2.95-2.84 (m, 2H), 2.58 (s, 3H), 1.70 (qd, 14.9 Hz, 2H), 1.38(t, J=7.0 Hz, 3H), 0.98 (t, J=7.3 Hz, 3H), LCMS (M+H)=224.1, purity=68%.

Example 4 4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxamide (8a) and4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylic acid (8b)

To a stirring solution of ethyl4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylate (7a) (13 g, 58.2mmol) in ethanol (30 mL), was added ammonium hydroxide (130 mL) and theresultant reaction mixture was heated to 100° C. for 16 h. The reactionmixture was concentrated under reduced pressure and the obtained crudecompound was used in the next step reaction without furtherpurification. MS indicates the presence of mixture of products (mixtureof 8a and 8b).

Example 5 4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxamide (8a)

The above mixture (8a+8b) in dimethylformamide (40 mL), was treated withHBTU (27.9 g, 73.84 mmol) and diisoproylamine (1.58 g, 123.08 mmol) andstirred for RT under nitrogen atmosphere. To this ammonium chloride(4.88 g, 92.22 mmol) was added and the resultant reaction mixture wasstirred at RT for 16 h. The reaction mixture was diluted with ethylacetate (300 mL) and washed with brine and dried over anhydrous sodiumsulfate and concentrated under reduced pressure. Purification was doneby ether washings (3×20 mL) to afford the title compound as a solid (9.2g). ¹H NMR (400 MHz, DMSO-d6) δ=11.61 (br s, 1H), 9.89 (s, 1H), 7.10 (brs, 2H), 2.80 (br t, J=7.4 Hz, 2H), 2.45 (s, 3H), 1.68-1.52 (m, 2H), 0.87(br t, J=7.2 Hz, 3H), Mass (M−H)=193.3.

Example 6 1-amino-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxamide(2a)

To a stirring solution of4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxamide (8a) (3.0 g, 15.46mmol) in NMP, was added potassium tert-butoxide (17 mL, 17.0 mmol, 1M)and stirred for 20° C. for 2 h. To this O-(4-nitrobenzoyl)-hydroxylamine(3.37 g, 18.55 mmol) in NMP was added slowly and the resultant reactionmixture was stirred at RT for 30 min. [Purple color reaction mixtureindicates the formation of product]. The reaction mixture was dilutedwith water (50 mL) and extracted with ethyl acetate (3×70 mL). Thecombined ethyl acetate layer was washed with brine and dried overanhydrous sodium sulfate and concentrated under reduced pressure.Purification was done by ether washings (3×30 mL) to afford the titlecompound as a solid. ¹H NMR (400 MHz, DMSO-d6) δ=11.61 (br s, 1H), 9.85(s, 1H), 7.87 (br s, 1H), 7.43 (br s, 2H), 2.93-2.83 (m, 2H), 2.41 (s,3H), 1.60-1.52 (m, 2H), 0.91 (br t, J=7.2 Hz, 3H), Mass (M+H)=210.3.

Example 7 5-(chlorosulfonyl)-2-ethoxybenzoic acid (9)

2-ethoxybenzoic acid (25 g) at 25° C. was added to a mixture of thionylchloride (11 mL), and chlorosulfonic acid (41.3 mL) and the resultantreaction mixture was stirred at RT for 16 h. An off white solid wasseparated out which is stirred for 1 h. And the reaction mixture wasquenched with ice (270 g) and water (60 mL). The obtained solid wasseparated by filtration and solid was washed with water (2×100 mL) anddried under vacuum to afford the title compound as a solid (30 g). ¹HNMR (400 MHz, CDCl₃) δ=8.83 (s, 1H), 8.20 (br d, J=8.8 Hz, 1H), 7.23 (d,J=8.8 Hz, 1H), 4.45 (q, J=6.6 Hz, 2H), 1.64 (t, J=6.6 Hz, 3H), LCMS(M−H)=263.1, purity=95%.

Example 8 2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)benzoic acid (10)

To a stirring solution of 5-(chlorosulfonyl)-2-ethoxybenzoic acid (9)(30 g) in water (124 mL) at 10° C., was added N-methyl piperazine (33.6mL) at 15-20° C. The resultant reaction mixture was stirred at 10° C.After 5 min the title compound started to crystallize and the reactionmixture was stirred for 2 h. The solid was separated by filtration; thesolid was washed with water and dried under vacuum. Purification wasdone by heating in acetone (100 mL) for 1 h. The suspension was cooledto RT, crystallized solid was separated by filtration and dried undervacuum to afford the title compound as a white solid (23 g). ¹H NMR (400MHz, DMSO-d6) δ=7.89 (br d, J=1.9 Hz, 1H), 7.81 (br dd, J=1.9, 8.8 Hz,1H), 7.35 (br d, J=8.8 Hz, 1H), 4.21 (q, J=6.8 Hz, 2H), 2.87 (br s, 4H),2.37 (br s, 4H), 2.14 (s, 3H), 1.36 (t, J=7.0 Hz, 3H), LCMS (M+H)=329.1,purity=88%.

Example 91-amino-N-(2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)benzoyl)-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxamide(11)

To a stirring solution of2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)benzoic acid (10) (3.01 g,9.186 mmol) in DMF, was added HBTU (5.79 g, 15.3 mmol) anddiisopropylethyl amine (2.46 g, 19.12 mmol) to this1-amino-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxamide (2a) (1.6 g,7.65 mmol) was added and the resultant reaction mixture was stirred atRT for 16 h. The reaction mixture was diluted with water and extractedwith ethyl acetate (2×100 mL). The combined ethyl acetate layer waswashed with brine, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. Purification by column chromatography (neutralalumina, 0.5% methanol in dichloromethane) afforded the title compoundas a solid (500 mg) [600 mg of amide (2a) was recovered]. ¹H NMR (400MHz, DMSO-d6) δ=11.42 (br s, 1H), 9.96 (s, 1H), 7.92-7.77 (m, 2H), 7.40(br d, J=8.8 Hz, 2H), 7.32 (br s, 1H), 4.27 (q, J=6.8 Hz, 2H), 2.90 (brs, 4H), 2.78 (br s, 2H), 2.44-2.29 (m, 7H), 2.15 (s, 3H), 1.56 (br dd,J=7.4, 14.4 Hz, 2H), 1.40 (br t, J=6.7 Hz, 3H), 0.89 (br t, J=7.2 Hz,3H), LCMS (M+H)=519.9.

Example 102-(2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazine-6-carbaldehyde(1j)

To a stirring solution of1-amino-N-(2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)benzoyl)-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxamide(11) (1.5 g, 2.89 mmol) in t-butanol (30 vol), was added potassiumhydroxide (2 g) and the resultant reaction mixture was heated to 100° C.for 2 days. The reaction mixture was cooled to RT and concentrated underreduced pressure, the obtained solid was purified by basic alumina byeluting with 0-0.5% methanol in dichloromethane to afford the titlecompound as a solid (500 mg) [SM was recovered by 2% methanol indichloromethane]. ¹H NMR (400 MHz, DMSO-d6) δ=11.78 (s, 1H), 10.12 (s,1H), 7.94-7.76 (m, 2H), 7.39 (br d, J=9.3 Hz, 1H), 4.28-4.16 (m, 2H),4.09 (q, J=5.1 Hz, 4H), 3.13-3.04 (m, 2H), 2.91 (br s, 4H), 2.68 (s,3H), 2.41-2.27 (m, 4H), 2.09 (s, 3H), 1.65 (br dd, J=7.2, 14.7 Hz, 2H),1.33 (br t, J=6.7 Hz, 3H), 0.89 (br t, J=7.2 Hz, 3H), Mass (M−H)=500.1.

Example 112-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-6-(hydroxymethyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(1b)

To a stirring solution of2-(2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde (1j) (400 mg, 0.798 mmol) in methanol, was added sodiumborohydride (75 mg, 1.996 mmol) and the resultant reaction mixture wasstirred at RT for 16 h. The reaction mixture was concentrated underreduced pressure and the obtained residue was diluted withdichloromethane (30 mL) and washed with brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. Purification bywashings with ether (3×6 mL) afforded the title compound as a solid (320mg). ¹H NMR (400 MHz, DMSO-d6) δ=11.39 (br s, 1H), 7.84 (br d, J=8.8 Hz,1H), 7.80 (d, J=1.9 Hz, 1H), 7.38 (br d, J=8.8 Hz, 1H), 4.66 (br t,J=5.1 Hz, 1H), 4.40 (s, 2H), 4.21 (q, J=6.8 Hz, 2H), 2.91 (br s, 4H),2.79 (br t, J=7.4 Hz, 2H), 2.44 (s, 3H), 2.36 (br s, 4H), 2.14 (s, 3H),1.70-1.49 (m, 2H), 1.33 (br t, J=7.0 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H),LCMS (M+H)=504.1, purity=97.2%.

Example 12(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)methylacetate (1c)

A solution of2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-6-(hydroxymethyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(1b) (100 mg, 0.198 mmol) in acetic anhydride (0.5 mL) was stirred at RTfor 16 h. The reaction mixture was diluted with water (10 mL) andextracted with dichloromethane (3×15 mL). The combined dichloromethanelayer was washed with water (5-6 times), dried over anhydrous sodiumsulfate and concentrated under reduced pressure. Purification was doneby washings with ether (2×2 mL) to afford the title compound as a solid(70 mg). ¹H NMR (400 MHz, DMSO-d6) δ=11.52 (s, 1H), 7.94-7.72 (m, 2H),7.39 (br d, J=8.8 Hz, 1H), 5.07 (s, 2H), 4.22 (q, J=6.5 Hz, 2H),3.05-2.70 (m, 6H), 2.45 (s, 3H), 2.37 (br s, 3H), 2.15 (s, 3H), 2.01 (s,3H), 1.70-1.53 (m, 2H), 1.34 (br t, J=6.7 Hz, 3H), 0.89 (br t, J=7.2 Hz,3H), LCMS (M+H)=546.3, purity=99.5%.

Example 132-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-6-(hydroxymethyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(12)

To a stirring solution of2-(2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1j) (200 mg, 0.39 mol) in ethanol (5 mL), was added tosyl hydrazine(81.77 mg, 0.43 mmol) and the resultant reaction mixture was heated to50° C. for 16 h. The reaction mixture was concentrated under reducedpressure to afford the title compound as an off white solid (250 mg).LC-MS (M+H)=669.2, purity˜94.3%.

Example 14 methyl2-((2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)methoxy)acetate(13)

To a stirring solution of2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-6-(hydroxymethyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(12) (150 mg, 0.224 mmol) in dioxane (8 mL), were added potassiumcarbonate (108 mg, 0.784 mmol) and methylglycolate (81 mg, 0.448 mmol).The resulted mixture was heated in a microwave at 120° C. for 1 h. Thereaction mixture was concentrated and the obtained crude was purified byprep TLC to afford the title compound as an off white solid (70 mg). ¹HNMR (400 MHz, DMSO-d6) δ=11.44 (s, 1H), 7.91-7.76 (m, 2H), 7.38 (d,J=8.8 Hz, 1H), 4.51 (s, 2H), 4.21 (q, J=7.0 Hz, 2H), 4.13 (s, 2H), 3.68(s, 3H), 2.91 (br s, 4H), 2.81 (br t, J=7.4 Hz, 2H), 2.44 (s, 3H),2.40-2.27 (m, 4H), 2.15 (s, 3H), 1.61 (br dd, J=7.4, 14.9 Hz, 2H), 1.33(t, J=6.7 Hz, 3H), 0.93-0.83 (m, 3H), Mass (M+H)=576.3.

Example 152-((2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)methoxy)aceticacid (1h)

To a stirring solution of methyl2-((2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)methoxy)acetate(13) (25 mg, 0.043 mmol) in 2:1 ratio of tetrahydrofuran and water(1+0.5 mL), was added lithium hydroxide (4.9 mg, 0.13 mmol) and theresultant reaction mixture was stirred at RT for 3 h. The reactionmixture was concentrated and the residue was neutralized with saturatedcitric acid and then extracted with dichloromethane (2×20 mL). Thecombined dichloromethane layer was washed with brine, dried over sodiumsulfate and concentrated under reduced pressure. Purification wascarried out by prep TLC to afford the title compound as a pale greensolid (10 mg). ¹H NMR (400 MHz, DMSO-d6) δ=11.37 (s, 2H), 7.97-7.71 (m,2H), 7.38 (br d, J=8.8 Hz, 1H), 4.51 (br s, 2H), 4.21 (q, J=6.8 Hz, 2H),3.62 (br s, 2H), 3.05-2.71 (m, 6H), 2.49-2.30 (m, 7H), 2.14 (s, 3H),1.60 (br d, J=6.5 Hz, 2H), 1.33 (br t, J=6.7 Hz, 3H), 0.86 (br d, J=2.3Hz, 3H), LCMS (M−H)=560.3, purity=97.8%

Example 162-((2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)methoxy)-N-hydroxy-N-methylacetamide(1i)

To a stirring solution of2-((2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)methoxy)aceticacid (1h) (15 mg, 0.0267 mmol) in dimethylformamide (1 mL), was addedHBTU (12 mg, 0.032 mmol) and DIPEA (6.9 mg, 0.05 mmol). The mixture wasthen added with hydroxylamine hydrochloride (2.7 mg, 0.032 mmol) and thereaction mixture was stirred at RT for 2 h. The reaction mixture wasquenched with ice water (5 mL) and extracted with ethyl acetate (2×10mL). The combined ethyl acetate layer was washed with brine, dried oversodium sulfate and concentrated under reduced pressure. Purification byprep TLC afforded the title compound as a pale brown solid (5 mg). ¹HNMR (400 MHz, DMSO-d6) δ=11.45 (s, 1H), 9.75 (br s, 1H), 7.94-7.76 (m,2H), 7.38 (d, J=8.8 Hz, 1H), 4.51 (s, 2H), 4.28-4.05 (m, 4H), 3.10 (s,3H), 2.91 (br s, 4H), 2.85-2.78 (m, 2H), 2.44 (s, 3H), 2.36 (br s, 4H),2.14 (s, 3H), 1.60 (br dd, J=7.4, 14.4 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H),0.87 (t, J=7.4 Hz, 3H), LCMS (M−H)=560.3, purity=98.2%.

Example 17(E)-2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1a)

To a stirring solution of2-(2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1j) (20 mg, 0.039 mmol) in pyridine (0.3 mL) was added hydroxylaminehydrochloride (3.7 mg, 0.05 mmol) and the reaction mixture was heated to80° C. for 4 h. Purification was done by prep TLC to afford the titlecompound as a white solid (10 mg). ¹H NMR (400 MHz, DMSO-d6) δ=11.57 (s,1H), 10.95 (s, 1H), 8.21 (s, 1H), 7.93-7.77 (m, 2H), 7.39 (br d, J=8.8Hz, 1H), 4.31-4.15 (m, 2H), 3.08-2.79 (m, 6H), 2.55 (br s, 3H), 2.37 (brs, 4H), 2.14 (s, 3H), 1.67-1.51 (m, 2H), 1.34 (br t, J=6.7 Hz, 3H), 0.87(br t, J=7.2 Hz, 3H) LCMS (M−H)=517.1, purity=96.8%.

Example 182-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylicacid (1d)

To a stirred suspension of 1j (200 mg) in acetone and water (1:1, 20 mL)was added a solution of KMnO₄ in acetone and water (1:1, 20 mL) over aperiod of 30 min, subsequently while addition the pH of the reactionmixture (pH−8) was adjusted to pH−5 by using a buffer solution (1NKH₂PO₄ and 1N HCl, pH−3.5). After completion of the addition thereaction mixture was stirred at RT for 2 h. On completion, the reactionmixture was quenched with 10% aq sodium bisulfate solution and themixture was concentrated to remove acetone at RT. The obtained aqueousmixture was saturated with NaCl and filtered. The residual solid wasstirred with 10% methanol in dichloromethane and filtered throughcelite. The filtrate was dried over anhydrous Na₂SO₄ and concentrated toafford compound 1d (120 mg) as white solid. ¹H NMR (400 MHz, DMSO-d6+onedrop of TFA) δ=7.96-7.88 (m, 2H), 7.43 (d, J=9.4 Hz; 1H), 4.23 (q, J=7.0Hz; 2H), 3.81 (br d, J=11.8 Hz; 2H), 3.49 (br d, J=11.8 Hz; 2H),3.25-3.06 (m, 4H), 2.81 (s, 3H), 2.70-2.55 (m, 5H), 1.69-1.57 (m, 2H),1.35 (t, J=6.9 Hz; 3H), 0.88 (t, J=7.3 Hz; 3H), LCMS (M+H)=518.1,purity=93.5%.

Example 19 methyl2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate(1f)

To a stirred solution of compound 1d (80 mg) in methanol, thionylchloride was added slowly at 0° C. and the reaction mixture was refluxedfor 16 h. On completion, the reaction mixture was concentrated andpurified by prep-HPLC to afford compound 1f (35 mg) as pale yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ=9.62 (s, 1H), 8.53 (d, J=2.4 Hz; 1H),7.87 (dd, J=2.4, 8.9 Hz; 1H), 7.15 (d, J=8.9 Hz; 1H), 4.34 (q, J=7.1 Hz;2H), 3.89 (s, 3H), 3.35-3.18 (m, 2H), 3.09 (br s, 3H), 2.76 (s, 2H),2.50 (br s, 3H), 2.28 (s, 2H), 1.78-1.66 (m, 2H), 1.61 (t, J=7.0 Hz;3H), 0.98 (t, J=7.4 Hz; 3H), LCMS (M+H)=532.1, purity=96.8%.

Example 20N-(benzyloxy)-2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxamide(1e)

To a stirred solution of compound 1f (100 mg) in DMF, HBTU (110 mg,0.288 mmol) was added followed by DIPEA (0.2 mL, 1.152 mmol) at RT andstirred for 15 min. To this solution O-benzyl hydroxylaminehydrochloride (1.1 mmol) was added and the reaction mixture was stirredat RT for 6 h. After completion, the reaction mixture was diluted withice cold water and filtered. The obtained residue was washed withdiethyl ether and dried to afford 1e (60 mg) as white solid. LCMS(M+H)=623.3, purity=95.1%.

Example 212-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-N-hydroxy-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxamide(1g)

To a stirred solution of 1e (70 mg) in methanol (2 mL), Pd(OH)₂ (20%w/w) was added and the reaction mixture was hydrogenated underatmospheric pressure for 1 h. After completion the reaction mixture wasfiltered through celite and the filtrate was concentrated. The crudematerial was purified by prep-TLC to afford 1g (14 mg) as pale yellowsolid (which develops colored spot on TLC after standing at refrigeratortemperature). ¹H NMR (400 MHz, DMSO-d6) δ=11.61 (s, 1H), 10.55 (br s,1H), 8.99 (d, J=1.9 Hz; 1H), 7.93-7.70 (m, 2H), 7.39 (d, J=8.9 Hz; 1H),4.21 (q, J=6.8 Hz; 2H), 3.38 (q, J=7.0 Hz; 2H), 2.99-2.80 (m, 3H), 2.48(s, 2H), 2.40-2.30 (m, 2H), 2.15 (s, 1H), 1.60 (br dd, J=7.4, 15.2 Hz;2H), 1.33 (t, J=6.9 Hz; 2H), 1.24 (br s, 1H), 1.09 (t, J=7.0 Hz; 2H),0.85 (t, J=7.3 Hz; 2H), LCMS (M+H)=533.1, purity=95%.

Example 22 Ethyl1-amino-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylate (14)

To a stirred solution of 190 mg (0.92 mmol) ethyl4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylate in 5 mL tert-butylmethyl ether 25 mg aliquat 336, 290 mg (5.3 mmol) NH4Cl, 2.5 mL 30%aqueous NaOH and 2.5 mL 9% aqueous NH4Cl were added. During 20 min. 5.8mL 9% NaOCl was added under vigorous stirring at room temperature. After3 hours the reaction mixture was extracted using ethyl acetate andbrine, dried with magnesium sulfate and the solvent removed underreduced pressure to afford 210 mg (quantitative) the title compound as awhite solid. ¹H NMR (300 MHz, DMSO-d6) δ=9.89 (s, 1H), 6.11 (s, 2H),4.27 (q, J=7.2 Hz; 2H), 2.98-2.86 (m, 2H), 2.48 (s, 3H), 1.64-1.48 (m,2H), 1.36-1.27 (m, 3H), 1.24 (br s, 1H), 0.90 (t, J=7.3 Hz; 3H). LCMS(M+H)=239.1, purity=94%.

Example 23 Ethyl4-formyl-3-methyl-1-(2-propoxybenzamido)-5-propyl-1H-pyrrole-2-carboxylate(15)

A solution of 200 mg (1 mmol) 2-propoxybenzoyl chloride in 2 mLdimethylformamide were added at 10° C. to 160 mg (1 mmol) Hunig's basein 2 mL dimethyl formamide. A solution of 210 mg (0.92 mmol) ethyl1-amino-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylate (14) in 2 mLdimethylformamide was added and the reaction mixture was stirred at roomtemperature for 3 hours. The reaction mixture was extracted with ethylacetate and washed with aqueous sodium carbonate, 0.5 N HCl and brine.The organic layer was dried with magnesium sulfate and the solventremoved under reduced pressure to give the crude product as a gum.Chromatography om silica using cyclohexane/ethyl acetate 3/1 afforded290 mg (79%) of the title compound as a white solid. ¹H NMR (500 MHz,CDCl₃) δ=10.19 (s, 1H), 8.26 (dd, J=2, 7 Hz; 1H), 7.54 (dd, J=8, 7 Hz;1H), 7.13 (t, J=7 Hz; 1H), 7.07 (d, J=8 Hz, 1H), 4.17 (t, J=7 Hz, 2H),4.16 (t, J=7 Hz, 2H), 2.79 (s, 3H), 3.18 (m, 2H), 1.81-1.74 (m, 4H),1.15 (t, J=7 Hz, 3H), 1.00 (t, J=7 Hz, 4H). LCMS (M+H)=401.2,purity=92%.

Example 244-formyl-3-methyl-1-(2-propoxybenzamido)-5-propyl-1H-pyrrole-2-carboxylicacid (16)

To a solution of 400 mg (1 mmol) ethyl4-formyl-3-methyl-1-(2-propoxybenzamido)-5-propyl-1H-pyrrole-2-carboxylate(15) in 1.5 mL water, 1.5 mL methanol and 1.5 mL tetrahydrofuran wasadded 1.5 mL 1 M sodium hydroxide aqueous solution. The reaction mixturewas stirred at 50° C. for 5 hours. Extraction with ethyl acetate, washedwith brine, dried with magnesium sulfate afforded after removal ofsolvent 370 mg (quantitative) the title compound as a white solid.

LCMS (M+H)=373.2, purity=96%.

Example 254-formyl-3-methyl-1-(2-propoxybenzamido)-5-propyl-1H-pyrrole-2-carboxamide(17)

A solution of 420 mg (1.2 mmol)4-formyl-3-methyl-1-(2-propoxybenzamido)-5-propyl-1H-pyrrole-2-carboxylicacid (16), 96 mg (1.84 mmol) ammonium chloride, 224 mg (1.46 mmol) HBOT,640 uL (3.7 mmol) N,N-diisopropylethylamin (Hunig's base) in 16 mLdimethylformamide was treated with 296 mg (1.44 mmol)N,N′-dicyclohexylcarbodiimide (DCC). The reaction mixture was stirredfor 5 hrs. at 50° C. Work up with ethyl acetate, brine wash and dryingof the organic phase with magnesium sulfate afforded 427 mg (96%) titlecompound as a white solid. LCMS (M+H)=372.2, purity=93%.

Example 265-methyl-4-oxo-2-(2-propoxyphenyl)-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(18)

600 mg (1.6 mmol)4-formyl-3-methyl-1-(2-propoxybenzamido)-5-propyl-1H-pyrrole-2-carboxamide(17) were dissolved in 60 mol polyethylene glycol (PEG 400). Thesolution was dried for 30 minutes at 90° C. and 8 mbar. 562 mg (5 mmol)potassium tert-butoxide were added and the reaction mixture was heatedat 8 mbar for 1 hour at 140° C. Dilution with water and extraction withethyl acetate afforded the crude product as a white solid.Chromatography on silica using ethyl acetate/cyclohexane 7/3 afforded490 mg (87%) title compound as a white solid. ¹H NMR (500 MHz, CDCl₃)δ=10.18 (s, 1H), 10.09 (s, 1H), 8.19 (dd, J=2, 7 Hz; 1H), 7.50 (dd, J=8,7 Hz; 1H), 7.13 (t, J=7 Hz; 1H), 7.06 (d, J=8 Hz, 1H), 4.16 (t, J=7 Hz,2H), 3.23 (t, J=7 Hz, 2H), 2.79 (s, 3H), 2.04-1.95 (m, 2H), 1.81-1.74(m, 2H), 1.15 (t, J=7 Hz, 3H), 1.00 (t, J=7 Hz, 4H). LCMS (M+H)=354.2,purity=97%.

Example 273-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxybenzene-1-sulfonylchloride (19)

44 mg (0.12 mmol) 5-methyl-4-oxo-2-(2-propoxyphenyl)-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(18) was treated at 0° C. with 250 uL (3.8 mmol) chlorosulfuric acid.After 2 hours at 0° C. the starting material was completely dissolvedresulting in a deep red solution. The reaction mixture was quenched withice and water and extracted with 20 mL methylene chloride. This extractwas directly used for the conversion to the sulfonamide.

Example 282-(5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1p)

A solution of 0.12 mmol3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxybenzene-1-sulfonylchloride (19) in 20 mL methylene chloride was treated at roomtemperature with a solution of 32 mg (0.25 mmol)2-(piperidin-4-yl)ethanol and 64 mg (0.63 mmol) trimethylamine in 2 mLmethylene chloride. After two hours at room temperature the reactionmixture was washed with diluted hydrochloric acid, dried with magnesiumsulfate and concentrated. Chromatography on silica usingcyclohexane/ethyl acetate 1/1 resulted in 61 mg (90%) title compound asa white solid. ¹H NMR (500 MHz, CDCl₃) δ=10.18 (s, 1H), 9.89 (s, 1H),8.50 (d, J=3 Hz, 1H), 7.86 (dd, J=3, 9 Hz, 1H), 7.16 (d, J=9 Hz, 1H),4.24 (t, J=7 Hz, 2H), 3.79 (d, J=12 Hz, 1H), 3.65 (t, J=7 Hz, 2H), 3.21(t, J=8 Hz, 2H), 2.78 (s, 3H), 2.32 (t, J=10 Hz, 2H), 1.80-1.15 (m,11H), 1.16 (t, J=8 Hz, 3H), 0.99 (t, J=8 Hz, 3H). LCMS (M+H)=545.2,purity=98%.

Example 29 2-(1-((3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl) sulfonyl)piperidin-4-yl)ethylnitrate (1q)

68 mg (0.125 mmol)2-(5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde (1p) in 20 mL methylene chloride was treated with 180 mg (0.69mmol) triphenylphosphine and 125 mg (0.69 mmol) N-bromosuccinimide atroom temperature. The reaction mixture was refluxed for 8 hours, afterwhich TLC showed complete conversation to2-(5-((4-(2-bromoethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]-triazine-6-carbaldehyde(20). Work-up with methylene chloride, washed with brine, dried withmagnesium sulfate and removal of solvent under reduced pressure gave acolorless gum, which was dissolved in 10 mL acetonitrile. 190 mg (1.1mmol) silver nitrate in 5 mL acetonitrile was added at room temperature.The reaction mixture was stirred for 3 days, worked up with ethylacetate ad brine washed. The organic phase was dried with magnesiumsulfate and the solvent removed under reduced pressure. Chromatographyon silica using ethyl acetate/cyclohexane 2/3 gave 45 mg (61%) titlecompound as a white solid. ¹H NMR (500 MHz, CDCl₃) δ=10.15 (s, 1H),10.09 (s, 1H), 8.50 (d, J=2 Hz, 1H), 7.85 (dd, J=2, 9 Hz, 1H), 7.16 (d,J=9 Hz, 1H), 4.47 (t, J=7 Hz, 2H), 4.22 (t, J=7 Hz, 2H), 3.83 (d, J=11Hz, 2H), 3.66 (m, 2H), 3.04 (t, J=8 Hz, 2H), 2.79 (s, 3H), 2.35-1.30 (m,12H), 1.16 (t, J=7 Hz, 3H), 0.98 (t, J=7 Hz, 3H). LCMS (M+H)=590.2,purity=96%.

Example 30(E)-2-(5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1r)

A solution of 40 mg 1p (0.07 mmol) in 10 mL ethanol was treated with 50%aqueous hydroxylamine. After 4 hours at room temperature the reactionmixture was extracted with ethyl acetate, washed with brine, dried withmagnesium sulfate and the solvent removed under reduced pressure.Chromatography on silica using cyclohexane/ethyl acetate 1/1 resulted in35 mg (85%) title compound as a white solid. ¹H NMR (500 MHz, CDCl₃)δ=9.98 (s, 1H), 8.42 (d, J=2 Hz, 1H), 8.26 (s, 1H), 7.82 (dd, J=2, 9 Hz,1H), 7.12 (d, J=9 Hz, 1H), 4.19 (t, J=7 Hz, 2H), 3.77 (d, J=11 Hz, 2H),3.65 (t, J=7 Hz, 2H), 3.00 (t, J=8 Hz, 2H), 2.57 (s, 3H), 2.31 (t, J=11Hz, 2H), 2.10-1.30 (m, 11H), 1.23 (t, J=7 Hz, 3H), 0.95 (t, J=8 Hz, 3H).LCMS (M+H)=560.3, purity=98%.

Example 31(E)-2-(1-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl)sulfonyl) piperidin-4-yl)ethyl nitrate (1v)

25 mg (0.04 mmol)2-(1-((3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethylnitrate (1q) was dissolved in 20 mL ethanol. 0.5 mL 50% aqueoushydroxylamine was added at room temperature. After 3 hours at roomtemperature the reaction mixture was taken up in ethyl acetate and brinewashed, dried over magnesium sulfate. The solvent was removed to give 22mg (86%) title compound. ¹H NMR (500 MHz, CDCl₃) δ=9.83 (s, 1H), 8.50(d, J=2 Hz, 1H), 8.29 (s, 1H), 7.85 (dd, J=2, 9 Hz, 1H), 7.16 (d, J=9Hz, 1H), 4.47 (t, J=7 Hz, 2H), 4.22 (t, J=7 Hz, 2H), 3.83 (d, J=11 Hz,2H), 3.66 (m, 2H), 3.04 (t, J=8 Hz, 2H), 2.35-1.30 (m, 11H), 1.16 (t,J=7 Hz, 3H), 0.98 (t, J=7 Hz, 3H). LCMS (M+H)=605.2, purity=92%.

Example 325-methyl-2-(5-((4-methylpiperazin-1-yl)sulfonyl)-2-propoxyphenyl)-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(11)

Following the procedure for 1p starting from 40 mg (0.11 mmol)5-methyl-4-oxo-2-(2-propoxyphenyl)-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(19) and using 87 mg (0.75 mmol) 1-methylpiperazine gave afterchromatography on silica using ethyl acetate/methanol (98/2) 46 mg (79%)title compound as a white solid. ¹H NMR (500 MHz, CDCl₃) δ=9.68 (s, 1H),8.51 (d, J=2 Hz, 1H), 7.83 (dd, J=2, 9 Hz, 1H), 7.16 (d, J=9 Hz, 1H),4.65 (s, 2H), 4.23 (t, J=7 Hz, 2H), 3.64 (s, 2H), 3.20-2.58 (m, 8H),3.14 (s, 3H), 2.95 (t, J=8 Hz, 2H), 2.58 (s, 3H), 2.00 (m, 2H), 1.72 (m,2H), 1.16 (t, J=7 Hz, 3H), 0.97 (t, J=7 Hz, 3H). LCMS (M+H)=516.2,purity=96%.

Example 332-(5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1m)

Following the procedure for 1p starting from 275 mg (0.78 mmol)5-methyl-4-oxo-2-(2-propoxyphenyl)-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde (18) and using 0.5 mL (4.0 mmol) 2-(piperazin-1-yl)ethanol gaveafter chromatography on silica using ethyl acetate/cyclohexane/methanol(40/60/3) 383 mg (90%) title compound as a colorless gum. ¹H NMR (400MHz, CDCl₃) δ=10.19 (s, 1H), 9.68 (s, 1H), 8.52 (d, J=2 Hz, 1H), 7.89(dd, J=2, 9 Hz, 1H), 7.18 (d, J=9 Hz, 1H), 4.39-4.34 (m, 2H), 3.59 (m,2H), 3.23 (t, J=7 Hz, 2H), 3.12 (brs, 4H), 2.79 (s, 3H), 2.64-2.58 (m,6H), 1.79-1.72 (m, 4H), 1.62 (t, J=7 Hz, 3H), 0.99 (t, J=7 Hz, 3H). LCMS(M+H)=546.2, purity=93%.

Example 342-(5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)-2-propoxyphenyl)-6-(hydroxymethyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(1n)

To a solution of 310 mg (0.57 mmol)2-(5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbal de-hyde (1m) in 35 mL ethanol was added 150 mg (4 mmol) sodiumborohydride. The reaction mixture was stirred over night at roomtemperature treated with 5 mL acetone and stirred for one hour. Thereaction mixture was concentrated under reduced pressure, the residuetaken up in ethyl acetate and the organic phase was washed with brineand dried with magnesium sulfate. Chromatography on silica using ethylacetate/cyclohexane/methanol (40/60/4) gave 245 mg (79%) title compoundas a white solid. ¹H NMR (400 MHz, CDCl₃) δ=9.68 (s, 1H), 8.52 (d, J=2Hz, 1H), 7.89 (dd, J=2, 9 Hz, 1H), 7.18 (d, J=9 Hz, 1H), 4.79 (s, 2H),4.39-4.34 (m, 2H), 3.59 (m, 2H), 3.23 (t, J=7 Hz, 2H), 3.12 (brs, 4H),2.79 (s, 3H), 2.64-2.58 (m, 6H), 1.79-1.72 (m, 4H), 1.62 (t, J=7 Hz,3H), 0.99 (t, J=7 Hz, 3H). LCMS (M+H)=548.2, purity=97%.

Example 35 Ethyl-3-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-hydroxypropanoate(1s)

To a solution of 420 uL (3 mmol) diisopropylamine in 15 mLtetrahydrofuran at −80° C. was added 1.88 mL butyllithium (3 mmol) inhexane. After 10 minutes 390 uL (4 mmol) ethyl acetate was added. 118 mg(0.234 mmol)2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde (1j) in 5 mL tetrahydrofuran was added after 10 minutes and thereaction mixture was kept at −80° C. for 2 hours. Work up with ethylacetate and brine, magnesium sulfate drying and removal of the solventunder reduced pressure gave a colorless gum. Chromatography on silicawith ethyl acetate/ethanol (5/1) gave 115 mg (83%) of the title compoundas a white solid. ¹H NMR (500 MHz, CDCl₃) δ=9.94 (s, 1H), 8.34 (d, J=2Hz, 1H), 7.77 (dd, J=2, 8.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 5.31 (m,1H), 4.34-4.30 (m, 2H), 4.21-4.16 (m, 2H), 3.05-2.90 (m, 4H), 2.63-2.48(m, 8H), 2.59 (s, 3H) (s, 3H), 2.26 (s, 3H), 1.57 (t, J=7 Hz, 3H), 1.28(t, J=7.5 Hz, 3H), 0.98 (t, J=7 Hz, 3H). LCMS (M+H)=590.2, purity=95%.

Example 363-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-N,3-dihydroxypropanamide (ft)

50 mg (0.085 mmol) ethyl2-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-hydroxyacetate (1s) was dissolvedin 5 mL ethanol. 1.5 mL aqueous 50% hydrazine hydrate was added at roomtemperature and the reaction mixture was stirred at 35° C. for fourdays. Solvent was partially removed under reduced pressure, and workedup using ethyl acetate and brine. The organic phase was dried withmagnesium sulfate and the solvent removed under reduced pressure.Chromatography on silica with ethyl acetate/methanol (1/2) gave 20 mg(41%) title compound as a colorless solid. ¹H NMR (500 MHz, CDCl₃)δ=13.2 (s, 1H), 9.73 (s, 1H), 8.49 (s, 1H), 7.53 (m, 1H), 7.15 (m, 1H),5.30 (m, 1H), 4.00-3.90 (m, 2H), 3.07-2.80 (m, 4H), 2.60-2.40 (m, 8H),2.60 (s, 3H) (s, 3H), 2.30 (s, 3H), 1.33 (t, J=7 Hz, 3H), 0.88 (t, J=7Hz, 3H). LCMS (M+H)=577.2, purity=92%.

Example 37(E)-5-methyl-2-(5-((4-methylpiperazin-1-yl)sulfonyl)-2-propoxyphenyl)-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-methyl oxime (1o)

30 mg (0.06 mmol)5-methyl-2-(5-((4-methylpiperazin-1-yl)sulfonyl)-2-propoxyphenyl)-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde,92 mg (1.1 mmol) methylhydroxylamine hydrochloride and 46 mg (1.15 mmol)sodium hydroxide in 4.5 mL PEG-400 were heated for 8 hours to 100° C.Work up with ethyl acetate and aqueous sodium carbonate solution, dryingof the organic phase with magnesium carbonate and removal of the solventunder reduced pressure gave 19 mg (60%) title compound. ¹H NMR (500 MHz,CDCl₃) δ=9.81 (s, 1H), 8.45 (d, J=2 Hz, 1H), 8.20 (s, 1H), 7.85 (dd,J=2, 9 Hz, 1H), 7.14 (d, J=9 Hz, 1H), 3.96 (s, 3H), 3.73-3.59 (m, 2H),3.09-3.00 (m, 4H), 2.63 (s, 3H), 2.53-2.50 (m, 4H), 2.29 (s, 3H),1.72-1.60 (m, 4H), 0.98 (t, J=7 Hz, 3H), 0.95 (t, J=8 Hz, 3H). LCMS(M+H)=545.2, purity=89%.

Example 383-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-hydroxypropanenitrile (1u)

To a solution of 420 uL (3 mmol) diisopropylamine in 15 mLtetrahydrofuran 1.88 mL butyllithium was added at −80° C. After 15minutes 0.5 mL acetonitrile were added and the solution stirred for 15minutes at −80° C. 90 mg (0.18 mmol)2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1j) was added in 5 mL tetrahydrofuran was added and the reactionmixture was warmed up to 0° C. Work up with ethyl acetate andchromatography on silica using ethyl acetate/aceton (2/1) gave 60 mg(60%) title compound as a white solid. ¹H NMR (500 MHz, CDCl₃) δ=9.90(s, 1H), 8.32 (d, J=2 Hz; 1H), 7.75 (dd, J=4, 9 Hz; 1H), 7.13 (d, J=9Hz; 1H), 5.19 (t, J=8 Hz, 1H), 4.35 (m, 2H), 3.00-2.70 (m, 8H), 2.47 (s,3H), 2.26 (s, 3H), 1.69-1.60 (m, 2H), 1.61 (t, J=7 Hz, 3H), 0.98 (t, J=7Hz, 3H). LCMS (M+H)=543.2, purity=92%.

Example 396-(1,3-dihydroxypropyl)-2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (1k)

To a solution of 45 mg (0.08 mmol) ethyl3-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-hydroxypropanoate(1s) was added 380 mg (10 mmol) sodium borohydride. The reaction mixturewas heated to reflux for 12 hours. At room temperature 3 mL action wasadded and the reaction mixture was warmed up to 50° C. for 30 minutes.Standard work up using ethyl acetate and aqueous sodium carbonateafforded after chromatography on silica with ethyl acetate/methanol(3/1) 15 mg title compound as a colorless resin. ¹H NMR (500 MHz, CDCl₃)δ=9.73 (s, 1H), 8.41 (d, J=2 Hz, 1H), 7.78 (dd, J=2, 9 Hz, 1H), 7.13 (d,J=9 Hz, 1H), 5.13 (dd, J=4, 10 Hz, 1H), 3.89 (m, 2H), 3.07-2.80 (m, 4H),2.55 (s, 3H) (s, 3H), 2.27 (s, 3H), 1.70-1.30 (m, 4H), 1.58 (t, J=7 Hz,3H), 0.98 (t, J=7 Hz, 3H). LCMS (M+H)=548.3, purity=92%.

Example 405-((4-(2-(Benzoyloxy)ethyl)piperazin-1-yl)sulfonyl)-2-ethoxybenzoic acid(21)

A solution of 5-(chlorosulfonyl)-2-ethoxybenzoic acid (9) (5.66 g, 21.43mmol) in dichloromethane (50 mL) was added to a cooled solution of2-(Piperazin-1-yl)ethyl benzoate (5.54 g, 23.67 mmol) and triethylamine(8.8 mL, 64.53 mmol) in dichloromethane (100 mL) at 0° C. The resultantreaction mixture was stirred at RT for 16 h. On completion, the reactionmixture was concentrated. The obtained residue was acidified with 5%aqueous citric acid solution and extracted with ethyl acetate (3×200mL). The combined ethyl acetate layers was washed with brine (50 mL),dried over anhydrous sodium sulfate and concentrated to afford the title21 (9.7 g) as brown solid. ¹H NMR (400 MHz, CDCl₃) δ=8.48 (br d, J=2.4Hz, 1H), 7.98 (br d, J=8.3 Hz, 2H), 7.91 (dd, J=2.2, 8.6 Hz, 1H),7.59-7.53 (m, 1H), 7.47-7.39 (m, 2H), 7.18-7.12 (m, 1H), 4.45 (br t,J=5.6 Hz, 2H), 4.41-4.33 (m, 2H), 3.12 (br s, 4H), 2.89 (br t, J=4.9 Hz,2H), 2.80 (br s, 4H), 1.59 (dt, J=2.7, 7.0 Hz, 3H). LCMS (M+H)=463.3,purity˜78%.

Example 41Ethyl-1-(5-((4-(2-(benzoyloxy)ethyl)piperazin-1-yl)sulfonyl)-2-ethoxybenzamido)-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylate(22)

To a stirring solution of5-((4-(2-(Benzoyloxy)ethyl)piperazin-1-yl)sulfonyl)-2-ethoxybenzoic acid(21) (3.5 g, 7.55 mmol) in DMF (35 mL), was added TBTU (4.85 g, 15.11mmol) and diisopropylethyl amine (3.96 mL, 22.67 mmol) to this 14 (2.15g, 9.07 mmol) was added and the resultant reaction mixture was stirredat RT for 16 h. The reaction mixture was diluted with water andextracted with ethyl acetate (3×200 mL). The combined ethyl acetatelayer was washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Purification by columnchromatography (100-200 mesh silica gel, 1-3% methanol indichloromethane as eluent) afforded the title compound 22 (3.8 g) asbrown gum. ¹H NMR (300 MHz, DMSO-d6) δ=11.43 (s, 1H), 10.00 (s, 1H),7.94-7.80 (m, 4H), 7.68-7.59 (m, 1H), 7.54-7.46 (m, 2H), 7.42 (d, J=8.8Hz, 1H), 4.46-4.24 (m, 4H), 4.17 (q, J=7.2 Hz, 2H), 2.97-2.90 (m, 4H),2.89 (s, 11H), 2.73 (s, 8H), 2.69 (s, 3H), 2.59 (br s, 2H), 2.54 (s,3H), 1.58 (br dd, J=7.3, 15.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.16 (t,J=7.2 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H), LC-MS (M+H)=684.0, purity˜85%.

Example 421-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)benzamido)-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylicacid (23)

To a solution of 22 (10.6 g, 15.54 mmol) in MeOH (100 mL) and H₂O (100mL), NaOH (10 g, w/w) was added and stirred at 60° C. for 6 h. Oncompletion, the reaction mixture was concentrated; the obtained aqueousresidue was acidified with 1N HCl. The obtained solid was filtered,dried and washed with Et₂O (3×20 mL) to afford 23 (4.1 g) as whitesolid. ¹H NMR (300 MHz, DMSO-d6) δ=11.48 (s, 1H), 10.00 (s, 1H),7.91-7.78 (m, 2H), 7.41 (d, J=8.8 Hz, 1H), 4.27 (q, J=7.0 Hz, 2H), 3.44(br s, 2H), 2.88 (br s, 6H), 2.54 (s, 3H), 2.39 (br d, J=12.1 Hz, 2H),1.68-1.50 (m, 2H), 1.40 (t, J=7.0 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H). LC-MS(M−H)=551.4, purity˜91%.

Example 431-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)benzamido)-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxamide(24)

To a stirring solution of 23 (1.68 g, 3.054 mmol) in DMF (8 mL), TBTU(1.96 g, 6.10 mmol) and DIPEA (2.9 mL, 15.27 mmol) was added and stirredat RT for 30 min. To the obtained reaction mixture NH₄Cl (0.5 g, 9.16mmol) was added and the mixture was stirred at RT for 16 h. Oncompletion, the reaction mixture was quenched with water (130 mL) andextracted with EtOAc (2×100 mL). The combined organic layer was washedwith water (2×40 mL), brine (30 mL), dried over anhydrous Na₂SO₄ andconcentrated. The obtained crude was purified by silica gel (230-400mesh) column chromatography using 10% Methanol in dichloromethane aseluent to afford the title compound 24 (2 g) as white solid. ¹H NMR (400MHz, CDCl₃) δ=10.80 (br s, 1H), 10.04 (s, 1H), 8.50 (d, J=2.4 Hz, 1H),7.89 (dd, J=2.4, 8.8 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 5.73 (br s, 2H),4.40 (q, J=7.2 Hz, 2H), 3.64 (t, J=5.4 Hz, 2H), 3.10 (br s, 4H), 2.70(br t, J=4.6 Hz, 4H), 2.67-2.61 (m, 2H), 2.56 (s, 3H), 1.65 (t, J=6.8Hz, 3H), 0.97 (t, J=7.3 Hz, 3H). LCMS (M+H)=550.4, purity˜96.5%.

Example 442-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1w)

A solution of 24 (200 mg, 0.36 mmol) in absolute ethanol (5 mL) wasadded 1M aqueous KOH solution (5 mL) and stirred at 95° C. in a sealedtube for 72 h. The reaction mixture was concentrated completely underreduced pressure. The crude was added water (5 mL) and stirred at RT for10 min; the resulted solid was filtered, washed with diethyl ether (3×5mL) and dried to afford the title 1w (110 mg) as brown solid. ¹H NMR(400 MHz, CDCl₃) δ=10.19 (s, 1H), 9.69 (s, 1H), 8.53 (d, J=2.4 Hz, 1H),7.89 (dd, J=2.4 Hz, 8.8 Hz; 1H), 7.18 (d, J=8.8 Hz, 1H), 4.39-4.34 (m,2H), 3.59 (m, 1H), 3.22 (t, J=7.2 Hz, 2H), 3.11 (brs, 4H), 2.64-2.57 (m,6H), 1.79-1.73 (m, 2H), 1.62 (t t, J=7.2 Hz, 3H), 0.99 (t, J=7.2 Hz,3H), LCMS (M+H)=532.4, purity˜99%.

Example 45(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1x)

To a stirring solution of2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1w) (80 mg, 0.15 mmol) in Ethanol (3 mL) and water (0.5 mL) was addedhydroxylamine hydrochloride (26.17 mg, 0.376 mmol) and the reactionmixture was heated to 85° C. for 5 h. On completion, the reactionmixture was concentrated under reduced pressure. The obtained residuewas stirred in water (1 mL), filtered, washed with diethyl ether (2×3mL) and dried to afford 1x (60 mg) as a white solid. ¹H NMR (400 MHz,DMSO-d6) δ=11.62 (s, 1H), 10.95 (s, 1H), 9.72 (brs, 1H), 8.21 (s, 1H),7.91-7.89 (m, 2H), 7.44 (d, J=8.8 Hz; 1H), 5.31 (br, 1H), 4.26-4.21 (m,2H), 3.77-3.69 (m, 4H), 3.54 (br, 2H), 3.19 (m, 4H), 2.96-2.92 (m, 2H),2.79-2.73 (m, 2H), 2.55 (s, 3H), 1.63-1.56 (m, 2H), 1.35 (t, J=6.8 Hz,3H), 0.88 (t, J=7.6 Hz, 3H), LCMS (M+H)=547.8, purity˜93.6% (mixture ofsyn & anti isomers).

Example 462-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-methyloxime (1y)

To a stirring solution of2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1w) (80 mg, 0.15 mmol) in ethanol (3 mL) and water (0.5 mL) was addedmethoxylamine hydrochloride (31.5 mg, 0.376 mmol) and the reactionmixture was heated to 85° C. for 4 h. On completion, the reactionmixture was concentrated under reduced pressure. The obtained residuewas stirred in water (1 mL), filtered, washed with diethyl ether (2×3mL) and dried to afford the title compound 1y (58 mg) as a white solid.¹H NMR (400 MHz, CDCl3) δ=8.23 (s, 1H), 8.06 (dd, J=2, 8.8 Hz, 1H), 7.18(d, J=8.8 Hz, 1H), 4.30 (q, J=6.8 Hz, 2H), 3.67-3.64 (m, 2H), 3.12-3.03(m, 5H), 2.76 (br, 4H), 2.66-2.64 (m, 2H, 2.61 (s, 3H), 1.73-1.67 (m,2H), 1.48 (t, J=6.8 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), LCMS (M+H)=561.37,purity˜96%.

Example 47(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-(2-hydroxyethyl) oxime (1z)

To a stirring solution of2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1w) (50 mg, 0.094 mmol) in ethanol (2 mL) and water (0.5 mL) was added2-Aminoxyethanol (25.4 mg, 0.33 mmol) and the reaction mixture washeated to 85° C. for 16 h. On completion, the reaction mixture wasconcentrated under reduced pressure. The obtained residue was stirred inwater (1 mL), filtered, washed with diethyl ether (2×3 mL). The obtainedcrude was further purified by PREP TLC using 25% Acetone indichloromethane as eluent to afford the title 1z (33 mg) as a whitesolid ¹H NMR (400 MHz, CDCl3) δ=11.62 (s, 1H), 8.30 (s, 1H), 7.86-7.82(m, 2H), 7.39 (d, J=8.8 Hz, 1H), 4.70-4.67 (m, 1H), 4.36-4.35 (m, 1H),4.24-4.19 (m, 2H), 4.09-4.07 (m, 2H), 3.68-3.67 (m, 2H), 3.44-3.41 (m,2H), 2.96-2.88 (m, 6H), 2.55 (s, 3H), 2.37-2.34 (m, 2H), 1.62-1.56 (m,2H), 1.33 (t, J=7.2 Hz, 3H), 0.88 (t, J=7.6 Hz, 3H), LCMS (M+H)=591.37,purity˜95.7%.

Example 48Methyl-3-ethyl-4-formyl-1-hydroxy-5-propyl-1H-pyrrole-2-carboxylate (25)

(Z)-ethyl 2-(hydroxyimino)-3-oxopentanoate (35 g, 219.99 mmol),(E)-hex-2-enal (50.9 mL, 439.9 mmol) in toluene, was addeddi-isopropylamine (6.2 mL, 43.99 mmol) and the resultant reactionmixture was stirred at RT for 16 h. The reaction mixture was quenchedwith aqueous Ammonium chloride solution (300 mL) and extracted withdichloromethane (2×300 mL). The combined dichloromethane layer waswashed with brine and dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Purification by columnchromatography (100-200 mesh silica gel, 0-5% ethyl acetate in pet etheras eluent) afforded the title compound 25 (31 g) as gum. ¹H NMR (400MHz, CDCl₃) δ=12.27 (br s, 1H), 9.94 (s, 1H), 3.97 (s, 3H), 3.02 (q,J=7.3 Hz, 2H), 2.98-2.92 (m, 2H), 1.77-1.63 (m, 2H), 1.19 (t, J=7.3 Hz,3H), 0.97 (t, J=7.3 Hz, 3H), Mass (M+H)=240.2.

Example 49 Methyl-3-ethyl-4-formyl-5-propyl-1H-pyrrole-2-carboxylate(26)

To a stirring solution of ethyl4-formyl-1-hydroxy-3-ethyl-5-propyl-1H-pyrrole-2-carboxylate (25) (10 g,41.84 mmol) in dichloromethane (800 mL) and acetic acid (40 mL), zincdust (27.4 g, 418.41 mmol) was added in portions and the resultantreaction mixture was stirred at RT for 8 h. The reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure.Purification of the crude by column chromatography (100-200 mesh silicagel, 5% methanol in dichloromethane as eluent) afforded the titlecompound 26 (7.5 g) as solid. [SM was recovered by eluting with 5% ethylacetate in pet ether as eluent]. ¹H NMR (400 MHz, CDCl₃) δ=10.01 (s,1H), 9.00 (br s, 1H), 3.88 (s, 3H), 3.07 (q, J=7.7 Hz, 2H), 2.91 (t,J=7.6 Hz, 2H), 1.76-1.65 (m, 2H), 1.20 (t, J=7.3 Hz, 3H), 0.99 (t, J=7.3Hz, 3H), LCMS (M+H)=224.3, purity˜96%.

Example 50Methyl-1-amino-3-ethyl-4-formyl-5-propyl-1H-pyrrole-2-carboxylate (27)

To a stirring solution of 26 (5 g, 22.42 mmol), in DMF (50 mL) at 0° C.,NaOH (4.48 g, 112.1 mmol) was added in portions. After addition themixture was stirred at 0° C. for 1 h before cooled it to −20° C. Theobtained mixture was treated with chloramine solution in MTBE (freshlyprepared from NH₄Cl (15 g) in MTBE (400 mL) added 30% aqueous ammonia(30 mL) and cooled to −20° C. To the mixture sodium hypochloritesolution (120 mL, commercial grade in water) was added drop wise. Afteraddition the reaction mixture was stirred at −20° C. for 1 h. The MTBElayer was separated from the biphasic mixture) was added slowly for 20min. After addition, the reaction mixture was allowed to stir at RT for3 h. On completion, the reaction mixture was quenched with water andseparated the organic layer. The MTBE layer was washed with 5% sodiumthiosulfate solution and water (100 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford the titlecompound 27 (5.2 g) as brown solid. ¹H NMR (400 MHz, CDCl₃) δ=9.97 (s,1H), 5.39 (s, 2H), 3.89 (s, 3H), 3.09-2.96 (m, 4H), 1.68-1.60 (m, 2H),1.21-1.12 (m, 3H), 0.98 (t, J=7.3 Hz, 3H), LCMS (M+H)=239.1, purity˜81%.

Example 51Methyl-1-(5-((4-(2-(benzoyloxy)ethyl)piperazin-1-yl)sulfonyl)-2-ethoxybenzamido)-3-ethyl-4-formyl-5-propyl-1H-pyrrole-2-carboxylate(28)

To a stirring solution of5-((4-(2-(Benzoyloxy)ethyl)piperazin-1-yl)sulfonyl)-2-ethoxybenzoic acid(21) (9.7 g, 20.99 mmol) in DMF (90 mL), was added HBTU (13.42 g, 41.9mmol) and diisopropyl ethyl amine (10.8 mL, 62.9 mmol) to this 27 (5.86g, 24.77 mmol) was added and the resultant reaction mixture was stirredat RT for 16 h. The reaction mixture was diluted with water andextracted with ethyl acetate (2×200 mL). The combined ethyl acetatelayer was washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Purification by columnchromatography (100-200 mesh silica gel, 0.5% methanol indichloromethane as eluent) afforded the title compound 28 (9.5 g) asbrown solid. ¹H NMR (400 MHz, CDCl₃) δ=10.41 (s, 1H), 10.06 (s, 1H),8.57 (d, J=2.4 Hz, 1H), 8.01-7.97 (m, 2H), 7.93 (dd, J=2.4, 8.3 Hz, 1H),7.60-7.52 (m, 1H), 7.47-7.38 (m, 2H), 7.18 (d, J=8.8 Hz, 1H), 4.49-4.33(m, 4H), 3.77 (s, 3H), 3.06 (br s, 5H), 2.78 (br t, J=5.6 Hz, 1H), 2.67(br s, 4H), 1.71-1.59 (m, 4H), 1.22 (t, J=7.6 Hz, 2H), 0.96 (t, J=7.3Hz, 3H), LCMS (M+H)=685.3, purity˜80%.

Example 521-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)benzamido)-3-ethyl-4-formyl-5-propyl-1H-pyrrole-2-carboxylicacid (29)

To a solution of 28 (9.5 g, 13.9 mmol) in MeOH (100 mL) and H₂O (100mL), NaOH (9.5 g, w/w) was added and stirred at 60° C. for 3 h. Oncompletion, the reaction mixture was concentrated; the obtained aqueousresidue was acidified with 1N HCl. The obtained solid was filtered,dried and washed with Et₂O (3×10 mL) to afford 29 (6 g) as white solid.¹H NMR (400 MHz, DMSO-d6) δ=9.96 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.82(dd, J=2.4, 8.8 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.27 (q, J=6.8 Hz, 2H),3.42 (br t, J=6.1 Hz, 4H), 3.06 (q, J=7.2 Hz, 2H), 2.93-2.75 (m, 6H),2.36 (t, J=6.1 Hz, 2H), 1.58 (qd, J=7.5, 15.1 Hz, 2H), 1.40 (t, J=7.1Hz, 3H), 1.10 (t, J=7.3 Hz, 3H), 0.89 (t, J=7.3 Hz, 3H), LC-MS(M+H)=565.5, purity˜88.2%.

Example 531-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)benzamido)-3-ethyl-4-formyl-5-propyl-1H-pyrrole-2-carboxamide(30)

To a stirring solution of 29 (6 g, 10.65 mmol) in DMF (60 mL), TBTU(6.84 g, 21.31 mmol) and DIPEA (9.46 mL, 31.95 mmol) was added andstirred at RT for 30 min. To the obtained reaction mixture NH₄Cl (1.14g, 21.31 mmol) was added and the mixture was stirred at RT for 16 h. Oncompletion, the reaction mixture was quenched with water (200 mL) andextracted with EtoAc (2×100 mL). The combined organic layer was washedwith water 2×50 mL), brine (30 mL), dried over anhydrous Na₂SO₄ andconcentrated. The obtained crude was purified by silica gel (230-400mesh) column chromatography using 10% Methanol in dichloromethane aseluent to afford the title compound 30 (3 g) as white solid. ¹H NMR (400MHz, CDCl₃) δ=10.70 (s, 1H), 10.04 (s, 1H), 8.54 (d, J=2.0 Hz, 1H), 7.92(dd, J=2.4, 8.8 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 5.59 (br s, 2H), 4.43(q, J=7.0 Hz, 2H), 3.59 (t, J=5.4 Hz, 2H), 3.15-2.89 (m, 6H), 2.72-2.51(m, 6H), 1.72-1.58 (m, 5H), 1.28 (t, J=7.3 Hz, 3H), 0.97 (t, J=7.3 Hz,3H), LCMS (M+H)=564.9, purity˜95.5%.

Example 542-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1aa)

A solution of 30 (300 mg, 0.53 mmol) in absolute ethanol (8 mL) wasadded 1M aqueous KOH solution (8 mL) and stirred at 95° C. in a sealedtube for 72 h. The reaction mixture was concentrated completely underreduced pressure. The crude was added water (8 mL) and stirred at RT for10 min, the resulted solid was filtered, washed with diethyl ether (3×4mL) and dried to afford the title 1aa (220 mg) as brown solid. ¹H NMR(300 MHz, CDCl3) δ=10.19 (s, 1H), 9.72 (brs, 1H), 8.55 (d, J=2.4 Hz,1H), 7.89 (dd, J=2.4 Hz, 8.8 Hz; 1H), 7.18 (d, J=8.7 Hz, 1H), 4.40-4.33(m, 2H), 3.58 (brs, 2H), 3.31-3.20 (m, 4H), 3.09 (brm, 4H), 2.63-2.54(m, 6H), 1.80-1.73 (m, 2H), 1.63 (t, J=7.2 Hz, 3H), 1.30 (t, J=7.4 Hz,3H), 1.00 (t, J=7.2 Hz, 3H), LCMS (M+H)=544.5, purity˜95%.

Example 55(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1ab)

To a stirring solution of2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1aa) (100 mg, 0.183 mmol) in ethanol (3 mL) and water (0.5 mL) wasadded hydroxylamine hydrochloride (70 mg, 0.458 mmol) and the reactionmixture was heated to 85° C. for 4 h. On completion, the reactionmixture was concentrated under reduced pressure. The obtained residuewas stirred in water (1 mL), filtered, washed with diethyl ether (2×3mL) and dried to afford the title 1ab (24 mg) as white solid. ¹H NMR(400 MHz, DMSO-d6) δ=11.64 (s, 1H), 10.95 (brs, 1H), 8.21 (s, 1H), 7.90(brs, 1H), 7.43 (br, 1H), 5.32 (br, 1H), 4.24-4.23 (m, 2H), 3.74-3.69(m, 3H), 3.53-3.36 (m, 2H), 3.19 (brm, 3H), 3.09-3.03 (m, 2H), 2.96-2.66(m, 5H), 1.63-1.57 (m, 2H), 1.36-1.33 (m, 3H), 1.14 (t, J=7.4 Hz, 3H),0.88 (t, J=7.4 Hz, 3H), LCMS (M+H)=561.3, purity˜94%+2.7% (mixture ofsyn & anti isomers).

Example 562-(2-Ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-methyloxime (1ac)

To a stirring solution of2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde (1aa) (100 mg, 0.183 mmol) in ethanol (2 mL) and water (0.5 mL)was added methoxylamine hydrochloride (38.3 mg, 0.458 mmol) and thereaction mixture was heated to 85° C. for 4 h. On completion, thereaction mixture was concentrated; the obtained crude was dissolved in10% methanol and dichloromethane (10 mL) mixture and washed with water(3 mL). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title 1ac (32 mg) asbrown solid. ¹H NMR (400 MHz, CD₃OD) δ=8.22 (s, 1H), 8.06 (d, J=2.4 Hz,1H), 7.93 (dd, J=2.4 Hz, 8.8 Hz; 1H), 7.37 (d, J=8.8 Hz, 1H), 4.30 (q,J=6.8 Hz, 2H), 3.91 (s, 3H), 3.66-3.63 (m, 2H), 3.15-3.04 (m, 8H),2.72-2.62 (m, 6H), 1.73-1.67 (m, 2H), 1.48 (t, J=7.4 Hz, 3H), 1.21 (t,J=7.2 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H), LCMS (M+H)=575.3,purity˜94.7%+4.7% (mixture of syn & anti isomers).

Example 57(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-(2-hydroxyethyl) oxime (1ad)

To a stirring solution of2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1aa) (80 mg, 0.146 mmol) in ethanol (3 mL) and water (0.5 mL) was added2-Aminoxyethanol (39.6 mg, 0.51 mmol) and the reaction mixture washeated to 85° C. for 16 h. On completion, the reaction mixture wasconcentrated; the obtained crude was purified by PREP HPLC using 4%methanol in dichloromethane to afford the title 1ad (20 mg) as a brownsolid. ¹H NMR (400 MHz, CD₃OD) δ=8.30 (s, 1H), 8.05 (d, J=2.4 Hz, 1H),7.92 (dd, J=2.4 Hz, 8.8 Hz; 1H), 7.36 (d, J=8.8 Hz, 1H), 4.30 (q, J=7.6Hz, 2H), 4.20-4.17 (m, 2H), 3.84-3.82 (m, 2H), 3.62-3.60 (m, 2H),3.15-3.04 (m, 6H), 2.62-2.61 (m, 4H), 2.53-2.50 (m, 2H), 1.73-1.68 (m,2H), 1.48 (t, J=6.8 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H), 0.96 (t, J=7.4 Hz,3H), LCMS (M+H)=605.8, purity˜93.6%.

Example 582-(5-((4-(2-chloroethyl)piperazin-1-yl)sulfonyl)-2-ethoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(31)

To a stirred solution of2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1w) (200 mg, 0.376 mmol) in dichloromethane (5 mL), was added SOCl₂(0.054 mL, 0.753 mmol) at 0° C. The reaction mixture was heated to 50°C. and stirred for 12 h. On completion, the reaction mixture wasconcentrated under reduced pressure. The obtained residue was dilutedwith water (10 mL) and extracted with dichloromethane (2×15 mL). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford the title compound 31 (200mg) as a brown solid, which was directly taken for next reaction withoutfurther purification. MS (M+H)=550.2.

Example 592-(4-((4-ethoxy-3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ae)

To a stirred solution of2-(5-((4-(2-chloroethyl)piperazin-1-yl)sulfonyl)-2-ethoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde (31) (200 mg, 0.364 mmol) in acetonitrile (5 mL), was addedAgNO₃ (247.5 mg, 1.457 mmol) at RT. The reaction was then heated to 50°C. and stirred for 16 h. On completion, the reaction mixture was cooledto RT and filtered through a celite bed. The filtrate was concentratedunder reduced pressure, diluted with water (15 mL) and extracted withethyl acetate (2×20 mL). The combined organic layers were dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford the crude product (260 mg; LCMS-82%) as an pale yellow solid. Aportion of the crude product (160 mg) was purified by reverse phasepreparative HPLC using 0.1% formic acid in water and acetonitrile toafford the title compound 1ae (23 mg) as an off-white solid. ¹H NMR (400MHz, CDCl₃) δ=10.19 (s, 1H), 9.69 (br s, 1H; D₂O exchangeable), 8.52 (d,J=2.4 Hz, 1H), 7.87 (dd, J=2.4, 8.8 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H),4.50 (t, J=5.4 Hz, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.22 (t, J=7.3 Hz, 2H),3.09-3.06 (m, 4H), 2.79 (s, 3H), 2.72 (t, J=5.4 Hz, 2H), 2.64-2.61 (m,4H), 1.78-1.75 (m, 2H), 1.63 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).LCMS (M+H)=577.7, purity˜94.2%.

Example 60(E)-2-(4-((4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1af)

To a stirred solution of2-(4-((4-ethoxy-3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ae) (100 mg, 0.173 mmol) in ethanol (2 mL) and water (0.5 mL),was added hydroxylamine hydrochloride (30.14 mg, 0.433 mmol) and thereaction mixture was heated to 85° C. for 8 h. On completion, thereaction mixture was concentrated under reduced pressure. The obtainedresidue was dissolved in water (5 mL) and extracted with ethyl acetate(2×15 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The obtained crude product waspurified by reverse phase preparative HPLC using 0.1% formic acid inwater and acetonitrile to afford the title compound 1ae (20 mg) as anoff-white solid. ¹H NMR (300 MHz, CD₃OD) δ=8.23 (s, 1H), 8.05 (d, J=1.8Hz, 1H), 7.91 (dd, J=1.8, 8.8 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 4.57 (t,J=5.3 Hz, 2H), 4.30 (q, J=6.9 Hz, 2H), 3.18-2.92 (m, 6H), 2.73 (t, J=5.3Hz, 2H), 2.64-2.60 (m, 7H), 1.73-1.70 (m, 2H), 1.48 (t, J=6.9 Hz, 3H),0.96 (t, J=7.5 Hz, 3H). LCMS (M+H)=592.4, purity˜92.3%+1.3% (mixture ofsyn & anti isomers).

Example 612-(5-((4-(2-chloroethyl)piperazin-1-yl)sulfonyl)-2-ethoxyphenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(32)

To a stirred solution of2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1aa) (200 mg, 0.366 mmol) in dichloromethane (5 mL), was added SOCl₂(0.053 mL, 0.733 mmol) at 0° C. The reaction mixture was heated to 50°C. and stirred for 12 h. On completion, the reaction mixture wasconcentrated under reduced pressure. The obtained residue was dilutedwith water (10 mL) and extracted with dichloromethane (2×15 mL). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford the title compound 32 (200mg) as a brown solid, which was directly taken for next reaction withoutfurther purification. LCMS (M+H)=564.2, purity˜86.6%.

Example 622-(4-((4-ethoxy-3-(5-ethyl-6-formyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ag)

To a stirred solution of2-(5-((4-(2-chloroethyl)piperazin-1-yl)sulfonyl)-2-ethoxyphenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(32) (200 mg, 0.355 mmol) in acetonitrile (5 mL), was added AgNO₃ (241mg, 1.420 mmol) at RT. The reaction was then heated to 50° C. andstirred for 16 h. On completion, the reaction mixture was cooled to RTand filtered through a celite bed. The filtrate was concentrated underreduced pressure, diluted with water (15 mL) and extracted with ethylacetate (2×20 mL). The combined organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by reverse phase preparative HPLC using 0.1% formicacid in water and acetonitrile to afford the title compound 1ag (30 mg)as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ=10.19 (s, 1H), 9.74 (br s,1H; D₂O exchangeable), 8.53 (d, J=2.2 Hz, 1H), 7.87 (dd, J=2.2, 8.8 Hz,1H), 7.18 (d, J=8.8 Hz, 1H), 4.51 (t, J=5.3 Hz, 2H), 4.37 (q, J=7.2 Hz,2H), 3.35-3.18 (m, 4H), 3.09-3.06 (m, 4H), 2.73 (t, J=5.3 Hz, 2H),2.63-2.61 (m, 4H), 1.78-1.75 (m, 2H), 1.63 (t, J=7.2 Hz, 3H), 1.30 (t,J=7.6 Hz, 3H), 1.00 (t, J=7.3 Hz, 3H). LCMS (M+H)=591.3, purity˜96.5%.

Example 63(E)-2-(4-((4-ethoxy-3-(5-ethyl-6-((hydroxyimino)methyl)-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ah)

To a stirred solution of2-(4-((4-ethoxy-3-(5-ethyl-6-formyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ag) (90 mg, 0.152 mmol) in ethanol (3 mL) and water (0.5 mL),was added hydroxylamine hydrochloride (26.4 mg, 0.380 mmol) and thereaction mixture was heated to 85° C. for 16 h. On completion, thereaction mixture was concentrated under reduced pressure. The obtainedresidue was dissolved in water (5 mL) and extracted with ethyl acetate(2×15 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The obtained crude product waspurified by reverse phase preparative HPLC using 0.1% formic acid inwater and acetonitrile to afford the title compound 1ah (23 mg) as abrown solid. ¹H NMR (300 MHz, CD₃OD) δ=8.22 (s, 1H), 8.05 (d, J=2.2 Hz,1H), 7.91 (dd, J=2.2, 8.8 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 4.57 (t,J=5.3 Hz, 2H), 4.31 (q, J=6.9 Hz, 2H), 3.20-2.92 (m, 8H), 2.73 (t, J=5.3Hz, 2H), 2.63-2.61 (m, 4H), 1.73-1.70 (m, 2H), 1.49 (t, J=6.9 Hz, 3H),1.22 (t, J=7.3 Hz, 3H), 0.96 (t, J=7.3 Hz, 3H). LCMS (M+H)=606.3,purity˜92.3%+3.4% (mixture of syn & anti isomers).

Example 64(E)-2-(4-(4-ethoxy-3-(6-((methoxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)phenylsulfonyl)piperazin-1-yl)ethylnitrate (1ai)

To a stirred solution of2-(4-(4-ethoxy-3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-j][1,2,4]triazin-2-yl)phenylsulfonyl)piperazin-1-yl)ethylnitrate (1ae) (90 mg, 0.164 mmol) in ethanol (5 mL) and water (0.5 mL),was added O-methoxylamine hydrochloride (34.4 mg, 0.412 mmol) and thereaction mixture was heated to 85° C. for 8 h. The reaction wasmonitored by LCMS. The reaction mixture was then cooled to roomtemperature and concentrated under reduced pressure. The obtainedresidue was dissolved in water (5 mL) and extracted with ethyl acetate(3×25 mL). The combined organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude LCMS analysis showed 45%of desired oxime along with 18% of chloro substituted oxime. Theobtained crude product was dissolved in acetonitrile (10 mL), addedAgNO₃ (80 mg) and stirred 50° C. for 12 h. The reaction mixture was thencooled to room temperature and concentrated under reduced pressure. Theobtained residue was dissolved in water (5 mL) and extracted with ethylacetate (3×25 mL).

The combined organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified byreverse phase preparative HPLC using 0.1% formic acid in water andacetonitrile to afford the title compound 1ai (18 mg) as an off-whitesolid. ¹H NMR (400 MHz, CD₃OD): δ 8.24 (s, 1H), 8.04 (d, J=2.4 Hz, 1H),7.91 (dd, J=2.4, 8.8 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 4.56 (t, J=5.1 Hz,2H), 4.34-4.24 (m, 2H), 3.91 (s, 3H), 3.17-2.94 (m, 6H), 2.77-2.68 (m,2H), 2.67-2.49 (m, 7H), 1.70 (dd, J=7.3, 14.7 Hz, 2H), 1.48 (t, J=7.1Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); LCMS (ES): m/z 606.3 [M+Et];purity˜95.1%+4.2% (mixture of anti & syn isomers).

Example 65(E)-2-(4-(4-ethoxy-3-(6-((2-hydroxyethoxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)phenylsulfonyl)piperazin-1-yl)ethylnitrate (1ak)

To a stirred solution of2-(4-(4-ethoxy-3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-j][1,2,4]triazin-2-yl)phenylsulfonyl)piperazin-1-yl)ethylnitrate (1ae) (105 mg, 0.182 mmol) in ethanol (5 mL) was added2-(aminoxy)ethanol (35.13 mg, 0.455 mmol) at room temperature andstirred at 80° C. for 8 h. After completion of reaction (monitored byTLC), the reaction mixture was concentrated under reduced pressure. Theobtained residue was purified by reverse phase preparative HPLC using0.1% formic acid in water and acetonitrile to afford the title compound1ak (28 mg) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.28 (s, 1H),8.03 (d, J=2.4 Hz, 1H), 7.90 (dd, J=2.4, 8.8 Hz, 1H), 7.37 (d, J=8.8 Hz,1H), 4.57 (t, J=5.1 Hz, 2H), 4.29 (q, J=7.0 Hz, 2H), 4.20-4.17 (m, 2H),3.83-3.81 (m, 2H), 3.03-3.01 (m, 6H), 2.74-2.71 (m, 2H), 2.61-2.59 (m,6H), 1.72-1.68 (m, 2H), 1.43 (t, J=7.0 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H);LCMS (ES): m/z 636.3 [M+Et]; purity˜94.4%+2.2% (mixture of anti & synisomers).

Example 66 tert-butyl 4-(2-(benzoyloxy)ethyl)piperidine-1-carboxylate(34)

To a stirred solution of tert-butyl4-(2-hydroxyethyl)piperidine-1-carboxylate (33) (8.5 g, 37.06 mmol) inTHF (160 mL), was added triethylamine (10.2 mL, 74.12 mmol) at roomtemperature. After 5 min, benzoyl chloride (4.73 mL, 40.77 mmol) wasadded dropwise at 0° C. under inert atmosphere. After addition, theresultant reaction mixture was stirred at room temperature for 2 h.After completion of reaction (monitored by TLC), the reaction wasquenched with water (75 mL) and extracted with ethyl acetate (2×100 mL).The combined organic layer was dried over anhydrous sodium sulphate andconcentrated under reduced pressure to afford 34 (10 g) as a brownliquid, which was directly taken for next reaction without furtherpurification. ¹H NMR (300 MHz, CDCl₃): δ 8.04 (d, J=7.3 Hz, 2H),7.58-7.50 (m, 1H), 7.49-7.41 (m, 2H), 4.38 (t, J=6.6 Hz, 2H), 4.12-4.08(m, 2H), 2.72-2.68 (m, 2H), 1.81-1.68 (m, 5H), 1.46 (s, 9H), 1.28-1.10(m, 2H).

Example 67 2-(piperidin-4-yl)ethyl benzoate. TFA salt (35)

To a stirred solution of compound 34 (10 g) in CH₂Cl₂ (100 mL), wasadded trifluoroacetic acid (6.89 mL, 90.09 mmol) dropwise at 0° C. underinert atmosphere. After addition, the resultant reaction mixture wasstirred at room temperature for 2 h. After completion of reaction(monitored by TLC), the reaction solution was concentrated under reducedpressure. The residue was co-distilled with CH₂Cl₂ (3×50 mL). The solidobtained was triturated with diethyl ether (50 mL), filtered and driedunder vacuum to afford title 35 (4 g, 33% in two steps) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (br s, 1H; D₂O exchangeable),8.85 (br s, 1H; D₂O exchangeable), 8.01-7.92 (m, 2H), 7.72-7.62 (m, 1H),7.59-7.48 (m, 2H), 4.34 (t, J=6.2 Hz, 2H), 3.23-3.21 (m, 2H), 2.86-2.81(m, 2H), 1.87 (br d, J=13.9 Hz, 2H), 1.81-1.63 (m, 3H), 1.43-1.26 (m,2H); LCMS (ES): m/z 234.1 [M+H⁺]; purity˜99%.

Example 685-(4-(2-(benzoyloxy)ethyl)piperidin-1-ylsulfonyl)-2-ethoxybenzoic acid(36)

To a stirred solution of 35 (4.07 g, 17.49 mmol) in CH₂Cl₂ (40 mL) wasadded triethylamine (11.10 mL, 79.54 mmol) at room temperature. Afteraddition, a solution of 9 (4.2 g, 15.90 mmol) in CH₂Cl₂ (20 mL) wasadded dropwise at 0° C. under inert atmosphere. The resultant reactionmixture was stirred at room temperature for 12 h. After completion ofreaction (monitored by TLC), the reaction mixture was concentrated anddiluted with saturated NaHCO₃ solution (50 mL). The resultant solutionwas then neutralized with saturated citric acid solution (50 mL) andextracted with ethyl acetate (3×200 mL). The combined organic layer wasdried over anhydrous sodium sulphate and concentrated under reducedpressure to afford Compound 36 (5.78 g, 78%) as a brown solid. ¹H NMR(300 MHz, DMSO-d₆): δ 13.02 (br s, 1H; D₂O exchangeable), 7.97-7.88 (m,3H), 7.81 (dd, J=2.4, 8.8 Hz, 1H), 7.68-7.60 (m, 1H), 7.55-7.46 (m, 2H),7.33 (d, J=8.8 Hz, 1H), 4.27 (t, J=6.4 Hz, 2H), 4.20 (q, J=7.0 Hz, 2H),3.61 (br d, J=11.7 Hz, 2H), 2.20 (br t, J=10.8 Hz, 2H), 1.79 (br d,J=11.7 Hz, 2H), 1.63 (q, J=6.4 Hz, 2H), 1.46-1 41 (m, 1H), 1.35 (t,J=7.0 Hz, 3H), 1.30-1.17 (m, 2H); LCMS (ES): m/z 462.2 [M+H⁺];purity˜95%.

Example 69 ethyl1-(5-(4-(2-(benzoyloxy)ethyl)piperidin-1-ylslfonyl)-2-ethoxybenzamido)-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylate(37)

To a stirred solution of5-(4-(2-(benzoyloxy)ethyl)piperidin-1-ylsulfonyl)-2-ethoxybenzoic acid(36) (4.2 g, 9.11 mmol) in DMF (30 mL), was added TBTU (5.85 g, 18.22mmol) and diisopropylethyl amine (4.7 mL, 27.33 mmol) at roomtemperature and stirred for 20 min. To this, ethyl1-amino-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylate (27) (2.168g, 9.11 mmol) was added and stirred the reaction mixture at roomtemperature for 16 h. After completion of reaction (monitored by TLC),the reaction was quenched with ice-cold water (100 mL) and extractedwith ethyl acetate (3×300 mL). The combined organic layer was dried overanhydrous sodium sulphate and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using10-50% ethyl acetate gradient in petroleum ether to afford the titlecompound 37 (3.0 g, 48%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ10.38 (s, 1H), 10.07 (s, 1H), 8.56 (d, J=2.2 Hz, 1H), 7.99 (d, J=7.3 Hz,2H), 7.93 (dd, J=2.4, 8.6 Hz, 1H), 7.59-7.50 (m, 1H), 7.48-7.36 (m, 2H),7.17 (d, J=8.8 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 4.33 (t, J=6.4 Hz, 2H),4.28-4.13 (m, 2H), 3.81 (br d, J=10.8 Hz, 2H), 2.61 (s, 3H), 2.30 (br t,J=10.8 Hz, 2H), 1.84-1.81 (m, 2H), 1.76-1.52 (m, 9H), 1.47-1.33 (m, 3H),1.27 (t, J=7.0 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); LCMS (ES): m/z 682.3[M+H⁺]; purity˜98%.

Example 701-(2-ethoxy-5-(4-(2-hydroxyethyl)piperidin-1-ylsulfonyl)benzamido)-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylicacid (38)

To a stirred solution of 37 (3.1 g, 4.55 mmol) in methanol (15 mL) andwater (15 mL), was added NaOH (3.1 g, w/w) at room temperature. Thereaction mixture was heated to 65° C. and stirred for 16 h. Aftercompletion of reaction (monitored by TLC), methanol was concentratedunder reduced pressure. The obtained aqueous reaction solution wasneutralized (pH˜7) with aqueous 1N HCl solution (10 mL). The solidprecipitated was filtered and dried under vacuum to afford 38 (2.6 g,87%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 12.89 (s, 1H;D₂O exchangeable), 11.45 (br s, 1H; D₂O exchangeable), 7.90 (d, J=2.2Hz, 1H), 7.83 (dd, J=2.2, 8.8 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.42 (brs, 1H; D₂O exchangeable), 4.26 (q, J=7.0 Hz, 2H), 3.60 (br d, J=11.4 Hz,2H), 3.43-3.37 (m, 2H), 2.86-2.83 (m, 2H), 2.54 (s, 3H), 2.19 (br t,J=10.8 Hz, 2H), 1.71 (br d, J=11.7 Hz, 2H), 1.64-1.51 (m, 2H), 1.40 (t,J=7.0 Hz, 3H), 1.36-1.26 (m, 3H), 1.25-1.03 (m, 3H), 0.90 (t, J=7.3 Hz,3H); LCMS (ES): m/z 550.3 [M+H⁺]; purity˜94%.

Example 711-(2-ethoxy-5-(4-(2-hydroxyethyl)piperidin-1-ylsulfonyl)benzamido)-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxamide(39)

To a stirred solution of 38 (2.4 g, 4.37 mmol) in DMF (25 mL), TBTU(2.80 g, 8.74 mmol) and diisopropylethylamine (2.3 mL, 13.11 mmol) wereadded and stirred at room temperature for 20 minutes. To this, ammoniumchloride (468 mg, 8.74 mmol) was added and the reaction mixture wasstirred at room temperature for 16 h. After completion of reaction(monitored by TLC), the reaction was quenched with ice-cold water (75mL) and extracted with 5% methanol in CH₂Cl₂ (2×100 mL). The combinedorganic layer was dried over anhydrous sodium sulphate and concentratedunder reduced pressure. The obtained crude product was purified bysilica gel column chromatography using 2-8% gradient methanol indichloromethane as eluent to afford the title compound 39 (2 g, 83%) asa pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.36 (s, 1H; D₂Oexchangeable), 9.96 (s, 1H), 7.88 (d, J=2.6 Hz, 1H), 7.86-7.81 (m, 1H),7.48 (br s, 1H; D₂O exchangeable), 7.39 (br d, J=8.8 Hz, 1H), 7.31 (brs, 1H; D₂O exchangeable), 4.35-4.19 (m, 2H+OH), 3.67-3.53 (m, 2H),3.43-3.34 (m, 2H), 2.93-2.72 (m, 2H), 2.41 (s, 3H), 2.31-2.13 (m, 2H),1.72 (br d, J=11.7 Hz, 2H), 1.62-1.50 (m, 2H), 1.40 (t, J=7.0 Hz, 3H),1.36-1.21 (m, 5H), 0.89 (t, J=7.2 Hz, 3H); LCMS (ES): m/z 549.3 [M+H⁺];purity˜91%.

Example 722-(2-ethoxy-5-(4-(2-hydroxyethyl)piperidin-1-ylsulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazine-6-carbaldehyde(40)

To a stirred solution of 39 (400 mg, 0.72 mmol) in absolute ethanol (6mL) was added 1M aqueous KOH solution (5 mL) and stirred at 100° C. in asealed tube for 96 h. The reaction mixture was concentrated completelyunder reduced pressure. The obtained residue was diluted with water (5mL) and stirred at room temperature for 10 min. The solid precipitatedwas filtered and dried to afford the title compound 40 (280 mg, 72%) asa brown solid. ¹H NMR (400 MHz, CDCl₃): δ 10.19 (s, 1H), 9.68 (br s, 1H;D₂O exchageable), 8.53 (d, J=2.0 Hz, 1H), 7.89 (dd, J=2.4, 8.8 Hz, 1H),7.16 (d, J=8.8 Hz, 1H), 4.36 (q, J=6.8 Hz, 2H), 3.81 (br d, J=11.7 Hz,2H), 3.68-3.64 (m, 2H), 3.22 (t, J=7.3 Hz, 2H), 2.79 (s, 3H), 2.40-2.27(m, 2H), 1.81-1.72 (m, 4H), 1.62 (t, J=6.8 Hz, 3H), 1.52-1.47 (m, 3H),1.42-1.33 (m, 3H), 0.99 (t, J=7.3 Hz, 3H); LCMS (ES): m/z 531.3 [M+H⁺];purity˜92%.

Example 73(E)-2-(2-ethoxy-5-(4-(2-hydroxyethyl)piperidin-1-ylsulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazine-6-carbaldehydeoxime (1al)

To a stirred solution of compound 40 (140 mg, 0.264 mmol) in ethanol (3mL) and water (0.5 mL), was added hydroxylamine hydrochloride (45.88 mg,0.66 mmol) and the reaction mixture was heated to 90° C. for 16 h. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure. The obtained residue was dissolvedin water (5 mL) and extracted with ethyl acetate (3×25 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The obtained crude product was purified by reversephase preparative HPLC using 0.1% formic acid in water and acetonitrileto afford the title compound 1al (80 mg, 55%) as an off-white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 11.55 (br s, 1H; D₂O exchageable), 10.95 (s,1H; D₂O exchageable), 8.21 (s, 1H), 7.92-7.79 (m, 2H), 7.37 (d, J=8.3Hz, 1H), 4.31 (t, J=5.1 Hz, 1H; D₂O exchageable), 4.21 (q, J=6.8 Hz,2H), 3.60 (br d, J=11.2 Hz, 2H), 3.39 (q, J=5.9 Hz, 2H), 2.94 (br t,J=7.6 Hz, 2H), 2.55 (s, 3H), 2.24 (br t, J=11.0 Hz, 2H), 1.76-1.52 (m,4H), 1.39-1.26 (m, 6H), 1.24-1.09 (m, 2H), 0.88 (t, J=7.3 Hz, 3H); LCMS(ES): m/z 546.3 [M+H⁺]; purity˜95.5%.

Example 742-(5-(4-(2-chloroethyl)piperidin-1-ylsulfonyl)-2-ethoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazine-6-carbaldehyde(41)

To a stirred solution of2-(2-ethoxy-5-(4-(2-hydroxyethyl)piperidin-1-ylsulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazine-6-carbaldehyde(40) (100 mg, 0.188 mmol) in dichloromethane (5 mL), was added SOCl₂(0.06 mL, 0.943 mmol) at room temperature. The reaction mixture washeated to 50° C. and stirred for 72 h. TLC showed product formationalong with unreacted 40. The reaction mixture was cooled to roomtemperature, added SOCl₂ (0.12 mL, 1.88 mmol) and the reaction mixturewas stirred at 80° C. for additional 48 h. The reaction mixture was thencooled to room temperature and concentrated under reduced pressure. Theobtained residue was diluted with water (10 mL) and extracted withdichloromethane (2×20 mL). The combined organic layer was dried overanhydrous sodium sulphate and concentrated under reduced pressure toafford the crude compound 41.

The reaction was repeated on 150 mg scale and both the crude materialswere combined and purified by reverse phase purification by Graceinstrument to afford the title compound 41 (120 mg) as an off-whitesolid. ¹H NMR (300 MHz, CDCl₃): δ 10.19 (s, 1H), 9.71 (s, 1H; D₂Oexchageable), 8.53 (d, J=2.2 Hz, 1H), 7.89 (dd, J=2.2, 8.8 Hz, 1H), 7.16(d, J=8.8 Hz, 1H), 4.36 (q, J=7.0 Hz, 2H), 3.84 (br d, J=11.7 Hz, 2H),3.54 (t, J=6.4 Hz, 2H), 3.22 (br t, J=7.3 Hz, 2H), 2.79 (s, 3H), 2.33(br t, J=11.4 Hz, 2H), 1.86-1.66 (m, 6H), 1.62 (t, J=7.0 Hz, 3H),1.45-1.26 (m, 3H), 1.00 (t, J=7.3 Hz, 3H); LCMS (ES): m/z 549.3 [M+H⁺];purity˜90%.

Example 752-(1-(4-ethoxy-3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)phenylsulfonyl)piperidin-4-yl)ethylnitrate (42)

To a stirred solution of 41 (140 mg, 0.255 mmol) in acetonitrile (5 mL),was added AgNO₃ (173.5 mg, 1.02 mmol) at room temperature. The reactionwas then heated to 60° C. and stirred for 48 h. TLC showed productformation along with unreacted 41. The reaction mixture was cooled toroom temperature, added AgNO₃ (260 mg, 1.53 mmol) and the reactionmixture was stirred at 60° C. for additional 48 h. The reaction mixturewas then cooled to room temperature and filtered though a celite bed.The filterate was concentrated under reduced pressure, diluted withwater (15 mL) and extracted with ethyl acetate (2×40 mL). The combinedorganic layers were dried over anhydrous sodium sulphate andconcentrated under reduced pressure. The crude product was purified bysilica gel purification by Grace instrument (20-50% gradientethylacetate in petroleum ether as an eluent) to afford the titlecompound 42 (56 mg) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃): δ10.19 (s, 1H), 9.73 (br s, 1H; D₂O exchageable), 8.52 (d, J=2.2 Hz, 1H),7.88 (dd, J=2.2, 8.8 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 4.46 (t, J=6.2 Hz,2H), 4.36 (q, J=7.0 Hz, 2H), 3.84 (br d, J=11.0 Hz, 2H), 3.22 (br t,J=7.3 Hz, 2H), 2.79 (s, 3H), 2.44-2.23 (m, 2H), 1.84-1.66 (m, 6H), 1.62(t, J=7.0 Hz, 3H), 1.44-1.41 (m, 3H), 0.99 (t, J=7.3 Hz, 3H); LCMS(M+H)=m/z 576.3 [M+H⁺]; purity˜91.4%.

Example 76(E)-2-(1-(4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)phenylsulfonyl)piperidin-4-yl)ethylnitrate (1am)

To a stirred solution of 42 (100 mg, 0.173 mmol) in ethanol (3 mL) andwater (0.5 mL), was added hydroxylamine hydrochloride (30.2 mg, 0.434mmol) and the reaction mixture was heated to 90° C. for 16 h. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure. The obtained residue was dissolvedin water (5 mL) and extracted with ethyl acetate (2×15 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The obtained crude product was purified by reversephase preparative HPLC using 0.1% formic acid in water and acetonitrileto afford the title compound 1am (56 mg) as a brown solid. ¹H NMR (300MHz, DMSO-d₆): δ 11.54 (s, 1H; D₂O exchageable), 10.95 (s, 1H; D₂Oexchageable), 8.21 (s, 1H), 7.95-7.79 (m, 2H), 7.37 (d, J=8.8 Hz, 1H),4.52 (br t, J=6.6 Hz, 2H), 4.21 (q, J=6.8 Hz, 2H), 3.63 (br d, J=12.2Hz, 2H), 2.94 (br t, J=7.3 Hz, 2H), 2.55 (s, 3H), 2.25 (br t, J=11.0 Hz,2H), 1.74 (br d, J=10.8 Hz, 2H), 1.67-1.53 (m, 4H), 1.35-1.30 (m, 4H),1.27-1.13 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); LCMS (M+H)=m/z 591.3 [M+H⁺];purity˜97.3%.

Example 77 tert-butyl 4-(3-(benzoyloxy)propyl)piperazine-1-carboxylate(43)

To a stirred solution of tert-butyl4-(3-hydroxypropyl)piperazine-1-carboxylate (7.0 g, 28.64 mmol) in THF(50 mL), was added triethylamine (8 mL, 57.29 mmol) at room temperature.After 5 min, benzoyl chloride (3.66 mL, 31.51 mmol) was added dropwiseat 0° C. under inert atmosphere. After addition, the resultant reactionmixture was stirred at room temperature for 1 h. After completion ofreaction (monitored by TLC), the reaction was quenched with water (100mL) and extracted with ethyl acetate (3×250 mL). The combined organiclayer was dried over anhydrous sodium sulphate and concentrated underreduced pressure to afford 43 (7.8 g) as a off-white solid. ¹H NMR (400MHz, CDCl₃): δ 8.06-8.00 (m, 2H), 7.59-7.52 (m, 1H), 7.48-7.40 (m, 2H),4.38 (t, J=6.6 Hz, 2H), 3.50-3.39 (m, 4H), 2.53 (t, J=7.3 Hz, 2H), 2.43(br t, J=4.9 Hz, 4H), 1.98 (quin, J=6.8 Hz, 2H), 1.46 (s, 9H); LCMS(M+H)=m/z 349.7 [M+H⁺]; purity˜83%.

Example 78 3-(piperazin-1-yl)propyl benzoate TFA Salt (44)

To a stirred solution of compound 43 (7.8 g) in CH₂Cl₂ (80 mL), wasadded trifluoroacetic acid (10.3 mL, 134.48 mmol) dropwise at 0° C.under inert atmosphere. After addition, the resultant reaction mixturewas stirred at room temperature for 8 h. After completion of reaction(monitored by TLC), the reaction solution was concentrated under reducedpressure. The residue was co-distilled with CH₂Cl₂ (3×100 mL). The solidobtained was triturated with diethyl ether (50 mL), filtered and driedunder vacuum to afford title 44 (8.6 g) as a white solid. ¹H NMR (300MHz, DMSO-d₆): δ 9.13 (br s, 2H), 8.07-7.95 (m, 2H), 7.73-7.64 (m, 1H),7.60-7.47 (m, 2H), 4.34 (t, J=6.2 Hz, 2H), 3.40-2.94 (m, 10H), 2.16-1.96(m, 2H); LCMS (M+H)=m/z 249.2 [M+H⁺]; purity˜98%.

Example 795-(4-(3-(benzoyloxy)propyl)piperazin-1-ylsulfonyl)-2-ethoxybenzoic acid(45)

To a stirred solution of Compound 44 (8.3 g, 31.43 mmol) in CH₂Cl₂ (60mL) was added triethylamine (26.5 mL, 188.63 mmol) at room temperature.After addition, a solution of 9 (8.57 g, 34.58 mmol) in CH₂Cl₂ (40 mL)was added dropwise at 0° C. under inert atmosphere. The resultantreaction mixture was stirred at room temperature for 16 h. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasconcentrated and diluted with saturated NaHCO₃ solution (50 mL). Theresultant solution was washed with ethyl acetate (100 mL). The aqueoussolution was then neutralized with saturated citric acid solution (100mL) and extracted with ethyl acetate (3×300 mL). The combined organiclayer was dried over anhydrous sodium sulphate and concentrated underreduced pressure to afford the title 45 (9.1 g, 60%) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 12.17 (br s, 1H), 8.35 (d, J=2.4 Hz, 1H),7.99 (d, J=7.3 Hz, 2H), 7.86 (dd, J=2.4, 8.8 Hz, 1H), 7.61-7.51 (m, 1H),7.47-7.36 (m, 2H), 7.12 (d, J=8.8 Hz, 1H), 4.43-4.26 (m, 4H), 3.21 (brs, 4H), 2.92 (br s, 4H), 2.86-2.78 (m, 2H), 2.15-2.05 (m, 2H), 1.55 (t,J=6.8 Hz, 3H); LCMS (ES): m/z 477.2 [M+H⁺]; purity˜97%.

Example 80 ethyl1-(5-(4-(3-(benzoyloxy)propyl)piperazin-1-ylsulfonyl)-2-ethoxybenzamido)-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylate(46)

To a stirred solution of5-(4-(3-(benzoyloxy)propyl)piperazin-1-ylsulfonyl)-2-ethoxybenzoic acid(45) (5.0 g, 10.50 mmol) in DMF (30 mL), was added TBTU (6.74 g, 21.0mmol) and diisopropylethyl amine (5.5 mL, 31.5 mmol) at room temperatureand stirred for 20 min. To this, ethyl1-amino-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylate (14) (2.50g, 10.5 mmol) was added and stirred the reaction mixture at roomtemperature for 16 h. After completion of reaction (monitored by TLC),the reaction was quenched with ice-cold water (100 mL) and extractedwith ethyl acetate (3×250 mL). The combined organic layer was dried overanhydrous sodium sulphate and concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography using30-50% ethyl acetate gradient in petroleum ether to afford the titlecompound 46 (4.8 g, 65%) as a brown liquid. ¹H NMR (300 MHz, CDCl₃): δ10.43 (s, 1H; D₂O exchageable), 10.07 (s, 1H), 8.57 (s, 1H), 7.99 (br d,J=7.7 Hz, 2H), 7.92 (br d, J=8.8 Hz, 1H), 7.64-7.50 (m, 1H), 7.49-7.36(m, 2H), 7.19 (d, J=8.8 Hz, 1H), 4.43 (q, J=6.6 Hz, 2H), 4.31 (br t,J=6.4 Hz, 2H), 4.23 (br d, J=5.5 Hz, 2H), 3.04 (br s, 4H), 2.61 (s, 3H),2.58-2.43 (m, 6H), 1.89 (td, J=6.6, 13.2 Hz, 2H), 1.73-1.57 (m, 5H),1.33-1.20 (m, 5H), 0.96 (t, J=7.3 Hz, 3H); LCMS (ES): m/z 697.9 [M+H⁺];purity˜89%.

Example 811-(2-ethoxy-5-(4-(3-hydroxypropyl)piperazin-1-ylsulfonyl)benzamido)-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylicacid (47)

To a stirred solution of 46 (2.8 g, 4.021 mmol) in methanol (30 mL) andwater (30 mL), was added NaOH (2.8 g, w/w) at room temperature. Thereaction mixture was heated to 65° C. and stirred for 12 h. Aftercompletion of reaction (monitored by TLC), methanol was concentratedunder reduced pressure. The obtained aqueous reaction solution wasneutralized (pH˜7) using aqueous 1N HCl solution (15 mL). The solidprecipitated was filtered and dried under vacuum to afford 47 (1.875 g,82%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.63 (br s,1H), 9.98 (s, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.83 (dd, J=2.2, 8.8 Hz, 1H),7.40 (d, J=8.8 Hz, 1H), 4.27 (q, J=6.8 Hz, 2H), 3.36 (br t, J=6.2 Hz,2H+OH), 2.88 (br s, 6H), 2.54 (s, 3H), 2.43 (br s, 4H), 2.31 (br t,J=7.2 Hz, 2H), 1.65-1.46 (m, 4H), 1.40 (t, J=7.0 Hz, 3H), 0.90 (t, J=7.3Hz, 3H); LCMS (ES): m/z 565.8 [M+H⁺]; purity˜96%.

Example 821-(2-ethoxy-5-(4-(3-hydroxypropyl)piperazin-1-ylsulfonyl)benzamido)-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxamide(48)

To a stirred solution of 47 (1.875 g, 3.32 mmol) in DMF (15 mL), TBTU(2.135 g, 6.64 mmol) and diisopropylethylamine (1.7 mL, 9.97 mmol) wereadded and stirred at room temperature for 20 minutes. To this, ammoniumchloride (356 mg, 6.64 mmol) was added and the reaction mixture wasstirred at room temperature for 16 h. After completion of reaction(monitored by TLC), the reaction was quenched with water (50 mL) andextracted with ethyl acetate (3×75 mL). The combined organic layer wasdried over anhydrous sodium sulphate and concentrated under reducedpressure. The obtained crude product was purified by silica gel columnchromatography using 4-8% gradient methanol in dichloromethane as aneluent to afford the title compound 48 (1.4 g, 74%) as a brown solid. ¹HNMR (400 MHz, CDCl₃): δ 10.61 (s, 1H; D₂O exchageable), 10.05 (s, 1H),8.51 (d, J=2.4 Hz, 1H), 7.89 (dd, J=2.4, 8.8 Hz, 1H), 7.17 (d, J=8.8 Hz,1H), 5.66 (br s, 2H; D₂O exchageable), 4.42 (q, J=7.2 Hz, 2H), 3.73 (t,J=5.1 Hz, 2H), 3.06-3.02 (m, 4H), 2.64-2.60 (m, 6H), 2.57 (s, 3H),1.74-1.61 (m, 7H), 0.97 (t, J=7.3 Hz, 3H); LCMS (ES): m/z 564.3 [M+H⁺];purity˜95%.

Example 832-(2-ethoxy-5-(4-(3-hydroxypropyl)piperazin-1-ylsulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazine-6-carbaldehyde(49)

To a stirred solution of 48 (500 mg, 0.88 mmol) in absolute ethanol (8mL) was added 1M aqueous KOH solution (8 mL) and stirred at 100° C. in asealed tube for 96 h. The reaction mixture was concentrated completelyunder reduced pressure. The obtained residue was diluted with water (10mL); the solid precipitated was filtered and dried to afford the titlecompound 49 (350 mg, 72%) as a pale yellow solid. ¹H NMR (300 MHz,CDCl₃): δ 10.18 (s, 1H), 8.47 (br s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.15(d, J=8.8 Hz, 1H), 4.37-4.33 (m, 3H), 3.73-3.70 (m, 2H), 3.21 (br t,J=7.2 Hz, 2H), 3.07-3.03 (m, 4H), 2.78 (s, 3H), 2.63-2.58 (m, 6H),1.89-1.50 (m, 7H), 0.99 (t, J=7.3 Hz, 3H); LCMS (ES): m/z 546.7 [M+H⁺];purity˜91%.

Example 84(E)-2-(2-ethoxy-5-(4-(3-hydroxypropyl)piperazin-1-ylsulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazine-6-carbaldehydeoxime (1an)

To a stirred solution of 49 (150 mg, 0.275 mmol) in ethanol (5 mL) andwater (0.5 mL), was added hydroxylamine hydrochloride (47.8 mg, 0.68mmol) and the reaction mixture was heated to 90° C. for 16 h. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure. The obtained residue was dissolvedin water (5 mL) and extracted 10% methanol in dichloromethane solution(3×25 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The obtained crude product waspurified by reverse phase preparative HPLC using 0.1% formic acid inwater and acetonitrile to afford the title compound 1an (62 mg, 40%) asan off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.56 (br s, 1H; D₂Oexchageable), 10.95 (br s, 1H; D₂O exchageable), 8.21 (s, 1H), 7.91-7.80(m, 2H), 7.39 (d, J=8.8 Hz, 1H), 4.34 (br s, 1H; D₂O exchageable), 4.22(q, J=7.0 Hz, 2H), 3.38-3.34 (m, 2H), 3.00-2.81 (m, 6H), 2.55 (s, 3H),2.43-2.40 (m, 4H), 2.35-2.27 (m, 2H), 1.62-1.58 (m, 2H), 1.54-1.45 (m,2H), 1.34 (t, J=7.0 Hz, 3H), 0.87 (t, J=7.3 Hz, 3H); LCMS (ES): m/z561.4 [M+H⁺]; purity˜95%.

Example 852-(5-(4-(3-chloropropyl)piperazin-1-ylsulfonyl)-2-ethoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazine-6-carbaldehyde(50)

To a stirred solution of2-(2-ethoxy-5-(4-(3-hydroxypropyl)piperazin-1-ylsulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazine-6-carbaldehyde(49) (200 mg, 0.366 mmol) in dichloromethane (10 mL), was added SOCl₂(0.1 mL, 1.83 mmol) at room temperature. The reaction mixture was heatedto 70° C. and stirred for 12 h. After completion of reaction (monitoredby TLC), the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The obtained residue was dilutedwith water (10 mL) and extracted with dichloromethane (2×25 mL). Thecombined organic layer was dried over anhydrous sodium sulphate andconcentrated under reduced pressure to afford the crude compound 50 (235mg) as a brown solid, which was directly taken for next reaction withoutfurther purification. ¹H NMR (300 MHz, CDCl₃): δ 9.64 (s, 1H), 8.48 (d,J=2.0 Hz, 1H), 7.84 (d, J=2.0, 8.8 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 4.34(q, J=6.8 Hz, 2H), 3.58-3.55 (m, 2H), 3.27-2.97 (m, 7H), 2.75 (s, 3H),2.58-2.54 (m, 4H), 1.82-1.72 (m, 2H), 1.67-1.53 (m, 6H), 1.02 (t, J=7.3Hz, 3H); LCMS (M+H)=m/z 564.3 [M+H⁺]; purity˜94%.

Example 863-(4-(4-ethoxy-3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)phenylsulfonyl)piperazin-1-yl)propylnitrate (51)

To a stirred solution of 8 (220 mg) in DMF (3 mL), AgNO₃ (266 mg, 1.56mmol) and NaI (58.5 mg, 0.39 mmol) were added at room temperature. Thereaction was then heated to 60° C. and stirred for 48 h. The reactionmixture was then cooled to room temperature, diluted with water (15 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere dried over anhydrous sodium sulphate and concentrated under reducedpressure to afford the crude compound 50.

Note: The same reaction was performed in two batches (100 mg+200 mg) andthe obtained crude materials were combined and purified by reverse phasepreparative HPLC using 0.1% formic acid in water and acetonitrile toafford the title compound 9 (52 mg) as a brown solid. LCMS (M+H)=m/z591.4 [M+H⁺]; purity˜97%.

Example 87(E)-3-(4-(4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazin-2-yl)phenylsulfonyl)piperazin-1-yl)propylnitrate (1ao)

To a stirred solution of 51 (50 mg, 0.084 mmol) in ethanol (2 mL) andwater (0.5 mL), was added hydroxylamine hydrochloride (15 mg, 0.211mmol) and the reaction mixture was heated to 90° C. for 12 h. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure. The obtained residue was dissolvedin water (2 mL) and extracted with 5% methanol in dichloromethane (3×25mL). The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The obtained crude product waspurified by reverse phase preparative HPLC using 0.1% formic acid inwater and acetonitrile to afford the title compound 1ao (10 mg) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.56 (br s, 1H; D₂Oexchageable), 10.95 (s, 1H; D₂O exchageable), 8.21 (s, 1H), 7.93-7.78(m, 2H), 7.39 (br d, J=8.8 Hz, 1H), 4.48 (br t, J=6.6 Hz, 2H), 4.29-4.15(m, 2H), 3.14-2.77 (m, 6H), 2.55 (s, 3H), 2.47-2.20 (m, 6H), 1.86-1.70(m, 2H), 1.59 (td, J=7.3, 14.7 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H), 0.87 (t,J=7.3 Hz, 3H); LCMS (M+H)=m/z 606.4 [M+H⁺]; purity˜95.8%.

Example 882-(2-ethoxy-5-((4-(3-hydroxypropyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(1ap)

In a reaction tube,2-(2-ethoxy-5-((4-(3-hydroxypropyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(49) (150 mg, 0.275 mmol), benzene (2.5 mL) and ethylene glycol (2.5 mL)were charged and stirred for 5 min. To this, pTSA.H₂O (75 mg, 0.399mmol) was added and capped the reaction tube. The reaction mixture wasdipped in a pre-heated oil bath at 140° C. and stirred for 16 h. Aftercompletion of reaction (monitored by TLC and LCMS analysis), thereaction mixture was cooled to room temperature and diluted with water(20 mL). The resultant solution was extracted with ethyl acetate (2×15mL). The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The obtained crude product waspurified by reverse phase preparative HPLC using 0.1% formic acid inwater and acetonitrile to afford 1ap (50 mg) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ=9.49 (br s, 1H; D₂O exchangeable), 8.50 (d, J=2.4 Hz,1H), 7.80 (dd, J=2.4, 8.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.17 (s, 1H),4.34 (q, J=7.0 Hz, 2H), 4.26 (br s, 1H; D₂O exchangeable), 3.72 (t,J=5.1 Hz, 2H), 3.07 (br s, 4H), 2.85 (t, J=7.6 Hz, 2H), 2.75-2.58 (m,6H), 2.54 (s, 3H), 1.84-1.65 (m, 4H), 1.61 (t, J=7.0 Hz, 3H), 1.01 (t,J=7.6 Hz, 3H); LCMS (ESI)=m/z 518.27, purity˜95.44%.

Example 89(Z)-2-(1-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethylnitrate (1aq)

1v (100 mg; 0.164 mmol) was dissolved in benzene (2 mL) at refluxtemperature under argon atmosphere. The reaction was then cooled to −50°C. and purged with dry HCl gas until the precipitation started to form(˜5 min). After the precipitation was observed, the reaction was cooledto 0° C. and stirred for 15 min. The solid was filtered, washed withbenzene (0.5 mL), petroleum ether (0.5 mL) and dried under vacuum. Thesolid was taken in diethyl ether (8 mL) and added pre-cooled 2.6 Maqueous NaOH solution (˜1.0 mL) at 0° C. until the solid was completelydissolved. Saturated NH₄Cl solution (˜2.0 mL) was added to it until theprecipitate forms and within 1 min, went back in to the solution. Thediethyl ether layer was separated and the aqueous layer was extractedwith diethyl ether (2×8 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under vacuum to afford the crudeproduct with LCMS-66% purity. The product was purified by reverse phasePrep HPLC (XBridge C18 column; 10 mM aqueous ammonium bicarbonatesolution with acetonitrile) to afford 1aq (17.5 mg) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H; D₂O exchangeable),11.18 (br s, 1H, D₂O exchangeable), 7.90-7.78 (m, 2H), 7.51 (s, 1H),7.36 (br d, J=9.3 Hz, 1H), 4.52 (br t, J=6.6 Hz, 2H), 4.11 (t, J=6.4 Hz,2H), 3.64-3.61 (m, 2H), 2.89-2.77 (m, 2H), 2.41 (s, 3H), 2.28-2.23 (m,2H), 1.82-1.66 (m, 4H), 1.65-1.51 (m, 4H), 1.38-1.31 (m, 1H), 1.25-1.19(m, 2H), 0.94 (t, J=7.3 Hz, 3H), 0.83 (t, J=7.3 Hz, 3H); LCMS (ES): m/z605.5 [M+H⁺]; purity˜95%.

Example 90 PDE5 Assay Purpose:

Evaluation of the effects of compounds of the present invention on theactivity of the human phosphodiesterase-5 quantified by measuring theformation of 5′GMP from cGMP using PDE5 enzyme isolated from humanplatelets. The latter was effected in accordance with the method asdescribed by Masaaki I, Nishikawa M, Fujioka M, Miyahara M, Isaka N,Shiku H, Nakano T, Cell Signal (1996), 8(8):575-581.

Experimental Protocol:

The test compound, i.e the compound of the present invention, referencecompound or water (control) are added to a buffer containing 40 mMTris/HCl (pH 7.8), 3 mM MgCl2, 1.4 mM DTT, 0.21% BSA, 200 mM NH4Cl, 1 μMcGMP and 0.1 μCi [3H]cGMP. Thereafter, the reaction is initiated byaddition of the enzyme and the mixture is incubated for 60 min at 22° C.

For basal control measurements, the enzyme is omitted from the reactionmixture. Following incubation SPA beads are added. After 20 min at 22°C. under shaking, the amount of [3H]5′GMP is quantified with ascintillation counter (Topcount, Packard).

The results shown in Table 1 are expressed as a percent inhibition ofthe control enzyme activity. The standard inhibitory reference compoundis dipyridamole, which is tested in each experiment at severalconcentrations to obtain an inhibition curve from which its IC50 valueis calculated. As shown in Table 1, the compounds of the presentinvention are potent and selective inhibitors of human cGMP-specificPDE5.

TABLE 1 Compound % inhibition at 5.0E−09M IC50 sildenafil 49.9 5.4 ×10⁻⁹M 1a 77.6 2.5 × 10⁻¹⁰M 1b 34.0 1.2 × 10⁻⁸M 1k 24.5 1n 33.0 1o 83.05.3 × 10⁻¹⁰M 1r 74.0 1.6 × 10⁻¹⁰M 1s 46.0 1t 44.9 1u 50.3 1.5 × 10⁻⁹M 1v45.9 4.1 × 10⁻⁹M 1w 75.5 1y 6.4 1z 87.0 1ab 86.8 1ac 12.4 1ad 50.5 1ae44.6 1af 74.5 1ag 18.7 1ah 69.7 1ai 0.3 1ak 8.3 1al 84.9 4.8 × 10⁻¹⁰M1am 25.1 6.6 × 10⁻⁸M 1an 84.9 4.2 × 10⁻¹⁰M 1ao 70.6 1.2 × 10⁻⁸M 1ap 69.22.8 × 10⁻⁹M 1aq 1.3

Example 91 Measurements of cGMP in Human Pulmonary Artery Smooth MuscleCells (hPASMC)

Human Pulmonary Artery Smooth Muscle Cells (hPASMC) were purchased fromClonetics™ Lonza (Lonza, reference number CC-2581) and cultured inClonetics™ smooth muscle growth medium (Clonetics™ SmGM™-2 withBulletKit™ growth factor supplements (Lonza, reference number CC-3182)at 37° C. in 5% CO₂. Culture medium was replaced each 48 hours. Cellswere grown in 75 cm² culture plates.

48 h before the experiments, cells were trypsinized (Trypsin kit OneReagentPack™ (CC-5034), Lonza) and plated in 96 well plates precoatedwith collagen I at 10000 cells per well. 24 h before the experimentsculture medium was replaced by serum-reduced (0.5% FBS) medium.Immediately before the experiments, medium was exchanged and hPASMCincubated in presence of the inventive compound 1v (in concentrations of1×10⁻¹²M (1 pM)-1×10⁻⁷M (100 nM)), the inventive compound 1r (inconcentrations of 1×10⁻¹⁶M (0.1 fM)-1×10⁻⁷M (100 nM)), the referencePDE5 inhibitor sildenafil (in concentrations of 1×10⁻¹⁰M (0.1nM)-1×10⁻⁷M (100 nM)) or vehicle (0.1% DMSO) over 15 or 30 min.

Measurements of intracellular cGMP were performed using the AmershamcGMP EIA System (GE Healthcare, RPN226) following the instructions ofthe manufacturer. The assay has a sensitivity of 2 fmol cGMP per well.Briefly, incubations were terminated by adding Amersham's lysis buffer 1and cells left for 10 min under agitation to ensure complete lysis. cGMPin samples was then acetylated using triethylamine and acetic anhydrideand determined by a competitive ELISA. The ELISA is based on thecompetition between acetylated cGMP in cell culture lysates and aperoxidase-labelled cGMP conjugate for limited binding sites on a cGMPspecific antiserum immobilized on pre-coated 96 well MTP. cGMP wasdetermined based on a standard curve. Results were expressed as fmolcGMP in 10⁴ cells as means+/−SE from 3 independent experiments intriplicates (FIG. 1A, FIG. 1B, FIG. 1C). Surprisingly, the inventivecompounds 1v and 1r, and in particular 1r, show a significantly higheractivity as compared to the reference inhibitor sildenafil.

Example 92 Isometric Tension Studies on Rat Aortic Rings Animals

A total of 131 male 11-week-old Sprague-Dawley rats from Harland(Barcelona) were used. The study was in line with the Guide for the Careand Use of Laboratory Animals (1996). After 1 week of acclimatization,rats were anesthetized. Appropriate depth of anesthesia was determinedby the absence of the leg flexor response and the eyelid reflex. Then,the thorax was quickly opened by a midline incision, and the rat wassacrificed by cutting the heart and exsanguination. The aorta wasquickly removed without damaging the endothelium and placed in a beakerfilled with Krebs's solution and bubbled with 95% O2/5% CO2.

Preparation of the Isolated Organs Rat Aortic Rings: Intact Endothelium

In brief, 3- to 4-mm thoracic aortic rings were mounted in separate 5-mlorgan baths containing Krebs solution with (mM) NaCl 118.0, KCl 4.7,CaCl2 1.9, KH2PO4 1.2, MgSO4 1.2, NaHCO₃25.0 and glucose 5.0 andmaintained at 37° C. and bubbled with 95% O2/5% CO2 (Klein T, Eltze M,Grebe T, Hatzelmann A, Komhoff M (2007). Celecoxib dilates guinea-pigcoronaries and rat aortic rings and amplifies NO/cGMP signaling by PDE5inhibition. Cardiovasc Res 75: 390-7). Indomethacin (1 μM) was added tothe saline solution.

The tissues were attached to force displacement transducers, stretchedto a resting tension of 1-1.5 g. Next, the endothelial integrity of thepreparations was determined by verifying the responsiveness toacetylcholine (ACh, 1 μM) in vessels precontracted with phenylephrine(PE, 300 nM, corresponding to 80-90% of its maximum effect). When therelaxation by 1 μM ACh of the tension achieved with 300 nM PE was morethan 60%, the preparation was eligible. Eligible rings were then washedseveral times to restore tension to the baseline level. After thisprocedure, the preparations were allowed to equilibrate for 60 minbefore contraction to a new single concentration of phenylephrine (300nM).

Rat Aortic Rings: Mechanically Removed Endothelium

In some experiments, the entire length of the thoracic aorta wasfunctionally denuded of the endothelial layer by gently scraping theluminal surface with a 1.5 mm glass rod. The tissues were attached toforce displacement transducers, stretched to a resting tension of 1-1.5g. Next, the absence of the endothelium was confirmed by verifying animpaired responsiveness to acetylcholine (1 μM) in vessels precontractedwith PE (300 nM). Rings were then washed several times to restoretension to the baseline level. After this response the preparations wereallowed to equilibrate for 60 min before contraction to a new singleconcentration of phenylephrine (300 nM; EC80-90 of its own maximaleffect).

Rat Aortic Rings: Endothelial Dysfunction Secondary to High Glucose

In brief, 3- to 4-mm thoracic aortic rings were mounted in separate 5-mlorgan baths containing Krebs' solution with (mM) NaCl 118.0, KCl 4.7,CaCl2 1.9, KH2PO4 1.2, MgSO4 1.2, NaHCO₃25.0 and glucose 5.0, maintainedat 37° C. and bubbled with 95% O2/5% CO2 [1]. Indomethacin (1 μM) wasadded to the saline solution. The tissues were attached to forcedisplacement transducers, stretched to a resting tension of 1-1.5 g.Next, the endothelial integrity of the preparations was determined byverifying the responsiveness to acetylcholine (1 μM) in vesselsprecontracted with PE (300 nM). Only vessels with at least 60%relaxation to 1 μM ACh from the tension with 300 nM were eligible.

Eligible rings were washed and equilibrated several times to restoretension to the baseline level with Krebs solution with (mM) NaCl 118.0,KCl 4.7, CaCl2 1.9, KH2PO4 1.2, MgSO4 1.2, NaHCO₃ 25.0 and glucose 25.0and maintained at 37° C., 95% O2/5% CO2. The preparations were allowedto equilibrate for 60 min in Krebs with high glucose (25 mM) beforecontraction to a new single concentration of PE (300 nM). Theexperimental protocol was a previously described (Dhar I, Dhar A, Wu L,Desai K (2012). Arginine attenuates methylglyoxal- and highglucose-induced endothelial dysfunction and oxidative stress by anendothelial nitric-oxide synthase-independent mechanism. J Pharmacol ExpTher 342: 196-204) with modifications.

Design Concentration Dependent Relaxation Curves Cumulative Protocol

In the first set of experiments, concentration-response curves (1 pM-1μM) for Sildenafil (reference), 1r, or 1v were constructed inendothelium-intact or -denuded preparations, in the presence ofN-nitro-L-arginine methyl ester (L-NAME 100 μM) or in Krebs with HighGlucose (25 mM). When the influence of NG-nitro-L-arginine methyl ester(L-NAME) on the relaxation induced by test and reference compounds(Sildenafil, 1r or 1v) was evaluated, L-NAME was added to thepreparations 30 min prior to PE. On the plateau of PE induced tensionthe compounds (sildenafil, 1r or 1v) were cumulatively added (30 min perconcentration) to the bath until maximum relaxation was achieved.Finally, sodium nitroprusside (0.1 mM) was added, in order to obtainmaximum relaxation of arterial rings.

The amount of relaxation (percent values as means±SEM) was quantified aspercent relaxation from the tension (plateau) achieved withphenylephrine.

Drugs

Compounds were dissolved in DMSO (100%) at 10 mM concentrations andstored in aliquots at −20° C. Dilutions were performed immediatelybefore each experiment and the DMSO concentration kept at 0.1% in allincubations.

Analysis of Results

Data are presented as mean±SEM. Statistical analysis of results has beenperformed by analysis of variance (ANOVA) either parametric ornon-parametric (Kruskal-Wallis), followed by Bonferroni test or Dunntests as appropriate (GraphPad Software Inc, San Diego, Calif., USA).Significance was accepted when P<0.05. Non-linear regression wasconducted with GraphPad Software). Results are related to Vehiclecontrol (0.1% DMSO) for each measurement point.

Results

FIG. 2 shows the concentration-dependent relaxation of phenylephrine(PE, 300 nM) precontracted rat aortic rings with intact endothelium(FIG. 2A), when rat aortic rings were pre-exposed to high (25 mM)glucose (FIG. 2B), in presence of the nitric oxide synthase inhibitorL-NAME (FIG. 2C) and in the absence of endothelium (FIG. 2D).

With intact endothelium (FIG. 2A) the inventive compounds 1v and 1r aremore potent and effective than Sildenafil. It is noteworthy that 1v wasalmost as potent and effective as 1r even though the potency to inhibitPDE5 of 1v was 40-fold higher than for 1r as shown in Table 1. Thesefindings may indicate that in the course of the exposure period, 1v wasin part converted into 1r secondary of its NO release.

Pre-exposure of rat aortic rings to high glucose (25 mM) is described toimitate a condition of hyperglycemia-induced endothelial dysfunction dueto a loss in endothelial nitric oxide generation (Dhar I, Dhar A, Wu L,Desai K (2012). Arginine attenuates methylglyoxal- and highglucose-induced endothelial dysfunction and oxidative stress by anendothelial nitric-oxide synthase-independent mechanism. J Pharmacol ExpTher 342: 196-204). FIG. 2B shows that under these conditions 1v wasclearly more potent and efficacious than 1r. In case of the latter, thelower potency and efficacy is most likely secondary to a loss of nitricoxide from endothelial cells resulting in less activation of the cGMPproducing soluble guanylate cyclase. In contrast, the superiority of 1vwhich comprises an additional ONO₂ group as compared to 1r is believedto be attributed to the NO release accompanying the PDE5 inhibition.These dual-pharmacology NO-releasing PDE5 inhibitors such as 1v arebelieved to be highly beneficial for the treatment of diabetic patients.Without being bound by this theory and notion, it is believed that oncein the aortic smooth muscle cell, 1v is ‘bio-activated’ byenzymatic/non-enzymatic processes into the more potent PDE5 inhibitor 1rand nitric oxide. This nitric oxide restores the compromised activity ofthe soluble guanylate cyclase and interacts with the PDE5 inhibitor in amore than additive fashion. This notion is confirmed under conditionswhen endothelial nitric oxide generation is blocked by the NOS inhibitorL-NAME (FIG. 2C) or following mechanical removal of the endothelium(FIG. 2D). Compared to intact endothelium the potency and efficacy ofthe pure PDE5 inhibitors 1r is largely impaired while the NO-releasingPDE5 inhibitor 1v is superior. FIG. 3 shows the non-linear regressionanalyses of the data presented in FIG. 2.

Potency (EC50), Efficacy (Emax) and concentrations where 40% relaxationwas achieved are summarized in Table 2.

Based on EC50 and Emax, 1v as compared to sildenafil (i) exerted anabout 17-fold more potent relaxation of PE-precontracted rat aorticrings in experiments with intact endothelium, (ii) revealed about95-fold more potent and more efficacious in relaxation of PEprecontracted rat aortic rings in the absence of endothelium, (iii) wasabout 22-fold more potent and more efficacious in relaxation of PEprecontracted rat aortic rings in the presence of L-NAME, (iv) mostimportantly, revealed about 110-fold more potent and more efficacious toexert relaxation of PE precontracted rat aortic rings with intactendothelium but pre-exposed to high (25 mM) glucose for 60 min prior theexperiment was commenced. Thus, related to the reference PDE5 inhibitorsildenafil the inventive NO releasing PDE5 inhibitor 1v achieved 40%relaxation in PE precontracted rat aortic rings (i) with intactendothelium, (ii) without endothelium, (iii) with L-NAME, (iv) with highglucose at about 24-fold, >130-fold, 68-fold, 1250-fold lowerconcentrations, respectively.

Collectively, these data strongly support the novel and inventivepreferred dual pharmacology approach of the present invention asexemplified and designed for 1v, or the corresponding nitrate-estercontaining PDE5 inhibitors of the present invention, to activate solubleguanylate cyclase and inhibit PDE5. Such a preferred dual pharmacologyapproach outperforms PDE5 inhibitors alone, in particular, in conditionsof endothelial dysfunction and when endogenous NO generation fromendothelial cells is impaired.

1. A compound of formula I

or pharmaceutically acceptable salt, solvate or hydrate thereof, whereinR₁ is C₁-C₃alkyl optionally substituted with F, C₃-C₆cycloalkyl,C₁-C₃alkoxy; X represents a bond or C₁-C₃alkylene optionally substitutedwith OH, ONO, ONO₂; R₂ is H, OH, ONO, ONO₂, C(O)OH, C(O)OC₁-C₃alkyl,CHO, CN, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl, CR₈═N—OR₉,CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂ or CR₈═N—ONO₂; R₃ is C₁-C₆alkyl optionallysubstituted with F, OH, ONO, ONO₂, C₁-C₃alkoxy, C₃-C₆cycloalkyl;C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl; R₄ is C₁-C₆alkyl optionallysubstituted with C₃-C₆cycloalkyl, C₁-C₆alkoxy, F, ONO, ONO₂;C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl; R₅ is H, SO₂NR₁₃R₁₄,NHSO₂NR₁₃R₁₄; R₆ is H or C₁-C₃alkyl; R₇ is H, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkyl substituted with phenyl, benzyl or a heterocyclic ring,wherein said phenyl, benzyl or said heterocyclic ring are independentlyoptionally substituted by C₁-C₃alkyl, F; R₈ is H, CH₃ or C₂H₅; R₉ is H,C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH,COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl; R₁₀ and R₁₁ are eachindependently H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂,CN, COOH, COOC₁-C₃, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇,OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl,OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl; or together with thenitrogen atom to which they are attached form a heterocyclic ring,wherein preferably said heterocyclic ring is selected from aziridine,azetidine, pyrollidine, piperidine, morpholine, piperazine andhomopiperazine, wherein said heterocyclic ring is optionally substitutedwith C₁-C₃ alkyl; R₁₂ is C₁-C₃ alkyl optionally substituted with OH,ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H,OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇,S(O₀₋₂)C₁-C₃alkyl; R₁₃ and R₁₄ are each independently H or C₁-C₆alkyloptionally substituted with F, OH, ONO, ONO₂, COOH, C₁-C₃alkoxy,C₃-C₆cycloalkyl; or together with the nitrogen atom to which they areattached form a heterocyclic ring, wherein preferably said heterocyclicring is selected from aziridine, azetidine, pyrollidine, piperidine,morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptaneand 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring isoptionally substituted with R₁₅; R₁₅ is C₁-C₆alkyl optionallysubstituted with halogen, OH, ONO, ONO₂, C₁-C₃ alkoxy, C₁-C₃haloalkoxy,COOR₁₆, NR₁₇R₁₈, C═NR₁₉, or with a tetrazole group which is optionallysubstituted with C₁-C₃alkyl; or a heteroaryl ring which is optionallysubstituted with F, wherein the at least one heteroatom of saidheteroaryl ring is nitrogen; R₁₆ is H, or C₁-C₄alkyl optionallysubstituted with F, OH, ONO, ONO₂, NR₁₇R₁₈, or with a heteroaryl ring,wherein the at least one heteroatom of said heteroaryl ring is nitrogen,and wherein preferably said heteroaryl ring is selected frompyrrolidine, piperidine, piperazine, morpholine, pyrrole, and imidazole,wherein nitrogen atom is directly bound to C₁-C₄ alkyl; R₁₇ and R₁₈ areeach independently H or C₁-C₄alkyl optionally substituted with ONO,ONO₂; R₁₉ is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂;C₃-C₆cycloalkyl.
 2. The compound according to claim 1 orpharmaceutically acceptable salt, solvate or hydrate thereof, wherein R₁is C₁-C₃alkyl.
 3. The compound according to any one of the claims 1 to2, or pharmaceutically acceptable salt, solvate or hydrate thereof,wherein R₃ is C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂,C₁-C₃alkoxy, C₃-C₆cycloalkyl, C₂-C₄alkenyl.
 4. The compound according toany one of the claims 1 to 3, or pharmaceutically acceptable salt,solvate or hydrate thereof, wherein R₄ is C₁-C₄alkyl optionallysubstituted with C₃-C₆cycloalkyl, C₁-C₃alkoxy, F, ONO, ONO₂;C₂-C₄alkenyl.
 5. The compound according to any one of claims 1 to 4, orpharmaceutically acceptable salt, solvate or hydrate thereof, whereinR₁₃ and R₁₄ together with the nitrogen atom to which they are attachedform a heterocyclic ring, wherein said heterocyclic ring is selectedfrom aziridine, azetidine, pyrollidine, piperidine, morpholine,piperazine, homopiperazine, 2,5-diazabicyclo-[2,2,1]heptane and3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring isoptionally substituted with R₁₅; R₁₅ is C₁-C₄alkyl optionallysubstituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, C₁-C₃haloalkoxy,COOR₁₆, NR₁₇R₁₈, C═NR₁₉; R₁₆ is H, or C₁-C₄alkyl optionally substitutedwith F, OH, ONO, ONO₂; R₁₇ and R₁₈ are each independently H orC₁-C₄alkyl optionally substituted with ONO, ONO₂; R₁₉ is C₁-C₄alkyloptionally substituted with F, ONO, ONO₂.
 6. The compound according toany one of claims 1 to 5, or pharmaceutically acceptable salt, solvateor hydrate thereof, wherein X—R₂ represents C₁-C₃alkylene optionallysubstituted with OH, ONO, ONO₂, CN, C(O)OH, C₁-C₂alkoxy,C(O)OC₁-C₃alkyl, C(O)N(R₆)OR₇, CHO, OC(O)H, OC₁-C₃alkylene-C(O)OH,OC₁-C₃alkylene-C(O)N(R₆)OR₇, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, CR₈═N—OR₉;C(O)OC₁-C₃alkyl, CHO, C(O)N(R₆)OR₇, S(O₀₋₂)C₁-C₃alkyl, CR₈═N—OR₉,CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂ or CR₈═N—ONO₂, wherein preferably said R₈ is Hor CH₃, and again further preferably wherein said R₆ is H or CH₃.
 7. Thecompound according to claim 1 or pharmaceutically acceptable salt,solvate or hydrate thereof, wherein said compound is selected from(E)-2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1a);2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-6-(hydroxymethyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(1b);(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)methylacetate (1c);2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylicacid (1d);N-(benzyloxy)-2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxamide(1e); Methyl2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate(10;2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-N-hydroxy-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxamide(1g);2-((2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)methoxy)aceticacid (1h);2-((2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)methoxy)-N-hydroxy-N-methylacetamide(1i);2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1j);6-(1,3-dihydroxypropyl)-2-(2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (1k);5-methyl-2-(5-(4-methylpiperazin-1-yl)sulfonyl)-2-propoxyphenyl)-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(11);2-(5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1m);2-(5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)-2-propoxyphenyl)-6-(hydroxymethyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(1n);(E)-5-methyl-2-(5-(4-methylpiperazin-1-yl)sulfonyl)-2-propoxyphenyl)-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-methyl oxime (1o);2-(5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1p);2-(1-((3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethylnitrate (1q);(E)-2-(5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1r);ethyl-3-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-hydroxypropanoate(1s);3-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-N,3-dihydroxypropanamide(10;3-(2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-hydroxypropanenitrile(1u);(E)-2-(1-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethylnitrate (1v);2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1w);(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1x);2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-methyloxime (1y);(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-(2-hydroxyethyl) oxime (1z);2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde(1aa);(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1ab);(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-methyl oxime (1ac);(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-5-ethyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeO-(2-hydroxyethyl) oxime (1ad);2-(4-((4-ethoxy-3-(6-formyl-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ae);(E)-2-(4-((4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1af);2-(4-((4-ethoxy-3-(5-ethyl-6-formyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ag);(E)-2-(4-((4-ethoxy-3-(5-ethyl-6-((hydroxyimino)methyl)-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ah);(E)-2-(4-((4-ethoxy-3-(6-((methoxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ai);(E)-2-(4-((4-ethoxy-3-(6-((2-hydroxyethoxy)imino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethylnitrate (1ak);(E)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (tat);(E)-2-(1-((4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethylnitrate (1am);(E)-2-(2-ethoxy-5-((4-(3-hydroxypropyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (tan);(E)-3-(4-((4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperazin-1-yl)propylnitrate (1ao);2-(2-ethoxy-5-((4-(3-hydroxypropyl)piperazin-1-yl)sulfonyl)phenyl)-5-methyl-7-propylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (1ap); and(Z)-2-(1-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethylnitrate (1aq).
 8. The compound according to claim 1 or pharmaceuticallyacceptable salt, solvate or hydrate thereof, wherein said compound isselected from(E)-2-(5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehydeoxime (1r); and(E)-2-(1-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethylnitrate (1v);
 9. A pharmaceutical composition comprising at least one ofthe compound of formula I of any one of the claims 1 to 8, or apharmaceutically acceptable salt, solvate or hydrate thereof, and apharmaceutically acceptable excipient, adjuvant, or carrier.
 10. Thecompound of formula I of any one of the claims 1 to 8, or thepharmaceutical composition of claim 9, or a pharmaceutically acceptablesalt, solvate or hydrate thereof, for use in a method of treating orpreventing a disease alleviated by inhibition of PDE-5 in a human or ina non-human mammal, preferably in a human.
 11. The compound for use, orthe pharmaceutical composition for use, according to claim 10, whereinsaid disease is selected from wound healing, chronic wound healing,diabetic foot, diabetic foot ulcer, leg ulcer, Raynaud's disease, maleerectile dysfunction, female sexual dysfunction, hair loss, skin aging,vascular aging, pulmonary artery hypertension; stable, unstable andvariant (Prinzmetal) angina; hypertension, pulmonary hypertension,chronic obstructive pulmonary disease, congestive heart failure, renalfailure, atherosclerosis, conditions of reduced blood vessel patency,peripheral vascular disease, vascular disorders, systemic sclerosis(SSc), scleroderma, morphea, inflammatory diseases, stroke, bronchitis,chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy,Idiopathic pulmonary fibrosis (IPF), peyronic's disease, glaucoma or adisease characterized by disorders of gut motility like irritable bowelsyndrome, liver fibrosis, Alzheimer's disease and chronic heart failure,wherein preferably said disease is selected from wound healing, chronicwound healing, diabetic foot, diabetic foot ulcer, leg ulcer, diabeticneuropathy, peripheral vascular disease, vascular disorders such asRaynaud's disease, systemic sclerosis (SSc), scleroderma, pulmonaryartery hypertension, male erectile dysfunction, and wherein againfurther preferably said disease is selected from wound healing, chronicwound healing, diabetic foot, diabetic foot ulcer, leg ulcer anddiabetic neuropathy.
 12. A compound of formula IV

wherein X, R₁, R₂, R₃, R₄, R₅ are defined as for the compound of formulain any one of the claims 1 to
 8. 13. A process for the preparation of acompound of formula I of any one of the claims 1 to 8,

wherein said process comprises: (a) reaction of a compound of formula IIwith a benzoic acid derivative of formula III in an aprotic or a proticsolvent to generate a compound of formula IV

(b) cyclization of said compound of formula IV to yield compound offormula I, wherein X, R₁, R₂, R₃, R₄, and R₅ are defined as for thecompound of formula I in any one of the claims 1 to
 8. 14. A process forthe preparation of a compound of formula I of any one of the claims 1 to8,

wherein said process comprises (a) reaction of a compound of formula VIwith a benzoyl chloride derivative of formula VIA to generate a compoundof formula VII

(b) hydrolysis of the ester compound of formula VII to an acidderivative of formula VIII

(c) amination of said compound of formula VIII to yield a compound offormula IV

(d) cyclization of said compound of formula IV to yield compound offormula I, wherein X, R₁, R₂, R₃, R₄, and R₅ are defined as for thecompound of formula I in any one of the claims 1 to 8; and wherein R′ isC₁-C₄ alkyl, benzyl, 4-alkoxybenzyl.
 15. A process for the preparationof a compound of formula I of any one of the claims 1 to 8,

wherein said process comprises conversion of compound of formula IA toyield compound of formula I

wherein X, R₁, R₂, R₃, R₄, and R₅ are defined as for the compound offormula in any one of the claims 1 to 8.